2024-03-29T06:47:31Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/2140702019-08-30T11:35:39Zcom_10033_620591col_10033_620599
Beyer, Tilo
Busse, Mandy
Hristov, Kroum
Gurbiel, Slavyana
Smida, Michal
Haus, Utz-Uwe
Ballerstein, Kathrin
Pfeuffer, Frank
Weismantel, Robert
Schraven, Burkhart
Lindquist, Jonathan A
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
2012-03-02T14:46:01Z
2012-03-02T14:46:01Z
2011-08
Integrating signals from the T-cell receptor and the interleukin-2 receptor. 2011, 7 (8):e1002121 PLoS Comput. Biol.
1553-7358
21829342
10.1371/journal.pcbi.1002121
http://hdl.handle.net/10033/214070
PLoS computational biology
T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells.
en
Cells, Cultured
Humans
Models, Biological
Phosphatidylinositol 3-Kinases
Protein Kinase C
Receptor Cross-Talk
Receptors, Antigen, T-Cell
Receptors, Interleukin-2
Reproducibility of Results
STAT Transcription Factors
Signal Transduction
T-Lymphocytes
src-Family Kinases
Integrating signals from the T-cell receptor and the interleukin-2 receptor.
Article2018-06-12T21:27:31ZT cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells.oai:repository.helmholtz-hzi.de:10033/2335722019-08-30T11:36:04Zcom_10033_620591col_10033_620599
Warnecke, Nicole
Poltorak, Mateusz
Kowtharapu, Bhavani S
Arndt, Boerge
Stone, James C
Schraven, Burkhart
Simeoni, Luca
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg 39120, Germany.
2012-07-13T09:44:08Z
2012-07-13T09:44:08Z
2012-04
TCR-mediated Erk activation does not depend on Sos and Grb2 in peripheral human T cells. 2012, 13 (4):386-91 EMBO Rep.
1469-3178
22344067
10.1038/embor.2012.17
http://hdl.handle.net/10033/233572
EMBO reports
Sos proteins are ubiquitously expressed activators of Ras. Lymphoid cells also express RasGRP1, another Ras activator. Sos and RasGRP1 are thought to cooperatively control full Ras activation upon T-cell receptor triggering. Using RNA interference, we evaluated whether this mechanism operates in primary human T cells. We found that T-cell antigen receptor (TCR)-mediated Erk activation requires RasGRP1, but not Grb2/Sos. Conversely, Grb2/Sos—but not RasGRP1—are required for IL2-mediated Erk activation. Thus, RasGRP1 and Grb2/Sos are insulators of signals that lead to Ras activation induced by different stimuli, rather than cooperating downstream of the TCR.
en
Archived with thanks to EMBO reports
TCR-mediated Erk activation does not depend on Sos and Grb2 in peripheral human T cells.
Article2012-11-15T00:00:00ZSos proteins are ubiquitously expressed activators of Ras. Lymphoid cells also express RasGRP1, another Ras activator. Sos and RasGRP1 are thought to cooperatively control full Ras activation upon T-cell receptor triggering. Using RNA interference, we evaluated whether this mechanism operates in primary human T cells. We found that T-cell antigen receptor (TCR)-mediated Erk activation requires RasGRP1, but not Grb2/Sos. Conversely, Grb2/Sos—but not RasGRP1—are required for IL2-mediated Erk activation. Thus, RasGRP1 and Grb2/Sos are insulators of signals that lead to Ras activation induced by different stimuli, rather than cooperating downstream of the TCR.oai:repository.helmholtz-hzi.de:10033/2449722019-08-30T11:35:39Zcom_10033_620591col_10033_620599
Togni, Mauro
Engelmann, Swen
Reinhold, Dirk
Schraven, Burkhart
Reinhold, Annegret
Institute for Molecular and Clinical Immunology, Otto von Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. annegret.reinhold@med.ovgu.de.
2012-09-19T12:59:43Z
2012-09-19T12:59:43Z
2012
The adapter protein ADAP is required for selected dendritic cell functions. 2012, 10 (1):14 Cell Commun. Signal
1478-811X
22672517
10.1186/1478-811X-10-14
http://hdl.handle.net/10033/244972
Cell communication and signaling : CCS
ABSTRACT:
en
Archived with thanks to Cell communication and signaling : CCS
The adapter protein ADAP is required for selected dendritic cell functions.
Article2018-06-12T22:13:39ZABSTRACT:oai:repository.helmholtz-hzi.de:10033/2678532019-08-30T11:36:05Zcom_10033_620591col_10033_620599
Mobashir, Mohammad
Schraven, Burkhart
Beyer, Tilo
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
2013-01-31T12:39:12Z
2013-01-31T12:39:12Z
2012
Simulated evolution of signal transduction networks. 2012, 7 (12):e50905 PLoS ONE
1932-6203
23272078
10.1371/journal.pone.0050905
http://hdl.handle.net/10033/267853
PloS one
Signal transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such biological processes, the receptors, after receiving the corresponding signals, activate a number of biomolecules which eventually transduce the signal to the nucleus. The main objective of our work is to develop a theoretical approach which will help to better understand the behavior of signal transduction networks due to changes in kinetic parameters and network topology. By using an evolutionary algorithm, we designed a mathematical model which performs basic signaling tasks similar to the signaling process of living cells. We use a simple dynamical model of signaling networks of interacting proteins and their complexes. We study the evolution of signaling networks described by mass-action kinetics. The fitness of the networks is determined by the number of signals detected out of a series of signals with varying strength. The mutations include changes in the reaction rate and network topology. We found that stronger interactions and addition of new nodes lead to improved evolved responses. The strength of the signal does not play any role in determining the response type. This model will help to understand the dynamic behavior of the proteins involved in signaling pathways. It will also help to understand the robustness of the kinetics of the output response upon changes in the rate of reactions and the topology of the network.
en
Archived with thanks to PloS one
Simulated evolution of signal transduction networks.
Article2018-06-12T17:24:28ZSignal transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such biological processes, the receptors, after receiving the corresponding signals, activate a number of biomolecules which eventually transduce the signal to the nucleus. The main objective of our work is to develop a theoretical approach which will help to better understand the behavior of signal transduction networks due to changes in kinetic parameters and network topology. By using an evolutionary algorithm, we designed a mathematical model which performs basic signaling tasks similar to the signaling process of living cells. We use a simple dynamical model of signaling networks of interacting proteins and their complexes. We study the evolution of signaling networks described by mass-action kinetics. The fitness of the networks is determined by the number of signals detected out of a series of signals with varying strength. The mutations include changes in the reaction rate and network topology. We found that stronger interactions and addition of new nodes lead to improved evolved responses. The strength of the signal does not play any role in determining the response type. This model will help to understand the dynamic behavior of the proteins involved in signaling pathways. It will also help to understand the robustness of the kinetics of the output response upon changes in the rate of reactions and the topology of the network.oai:repository.helmholtz-hzi.de:10033/2942812019-08-30T11:35:39Zcom_10033_620591col_10033_620599
Smida, Michal
Cammann, Clemens
Gurbiel, Slavyana
Kerstin, Nadja
Lingel, Holger
Lindquist, Sabine
Simeoni, Luca
Brunner-Weinzierl, Monika C
Suchanek, Miloslav
Schraven, Burkhart
Lindquist, Jonathan A
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, 39120, Germany. jon.lindquist@med.ovgu.de.
2013-06-20T09:16:48Z
2013-06-20T09:16:48Z
2013
PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells. 2013, 11 (1):28 Cell Commun. Signal
1478-811X
23601194
10.1186/1478-811X-11-28
http://hdl.handle.net/10033/294281
Cell communication and signaling : CCS
PAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation.
en
Archived with thanks to Cell communication and signaling : CCS
PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells.
Article2018-06-13T00:19:13ZPAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation.oai:repository.helmholtz-hzi.de:10033/3114112019-08-30T11:28:51Zcom_10033_620591col_10033_620725
Nandakumar, Ramya
Finsterbusch, Katja
Lipps, Christoph
Neumann, Berit
Grashoff, Martina
Nair, Sharmila
Hochnadel, Inga
Lienenklaus, Stefan
Wappler, Ilka
Steinmann, Eike
Hauser, Hansjörg
Pietschmann, Thomas
Kröger, Andrea
Helmholtz Centre for infection research, D38124 Braunschweig, Germany
2014-01-16T15:27:18Z
2014-01-16T15:27:18Z
2013-12
Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms. 2013, 145 (6):1414-23.e1 Gastroenterology
1528-0012
23973921
10.1053/j.gastro.2013.08.037
http://hdl.handle.net/10033/311411
Gastroenterology
Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication.
en
Archived with thanks to Gastroenterology
Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.
Article2018-06-13T09:08:20ZCurrent treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication.oai:repository.helmholtz-hzi.de:10033/3152402019-08-30T11:35:39Zcom_10033_620591col_10033_620725
Nair, Sharmila
Michaelsen-Preusse, Kristin
Finsterbusch, Katja
Stegemann-Koniszewski, Sabine
Bruder, Dunja
Grashoff, Martina
Korte, Martin
Köster, Mario
Kalinke, Ulrich
Hauser, Hansjörg
Kröger, Andrea
Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany
2014-04-03T14:17:07Z
2014-04-03T14:17:07Z
2014-03
Interferon regulatory factor-1 protects from fatal neurotropic infection with vesicular stomatitis virus by specific inhibition of viral replication in neurons. 2014, 10 (3):e1003999 PLoS Pathog.
1553-7374
24675692
10.1371/journal.ppat.1003999
http://hdl.handle.net/10033/315240
PLoS pathogens
The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.
en
Archived with thanks to PLoS pathogens
Interferon regulatory factor-1 protects from fatal neurotropic infection with vesicular stomatitis virus by specific inhibition of viral replication in neurons.
Article2018-06-12T22:31:56ZThe innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.oai:repository.helmholtz-hzi.de:10033/3250372019-08-30T11:33:56Zcom_10033_620591col_10033_620599
Wolleschak, Denise
Mack, Thomas S
Perner, Florian
Frey, Stephanie
Schnöder, Tina M
Wagner, Marie-Christine
Höding, Christine
Pils, Marina C
Parkner, Andreas
Kliche, Stefanie
Schraven, Burkhart
Hebel, Katrin
Brunner-Weinzierl, Monika
Ranjan, Satish
Isermann, Berend
Lipka, Daniel B
Fischer, Thomas
Heidel, Florian H
2014-08-21T10:32:29Z
2014-08-21T10:32:29Z
2014-06
Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function. 2014, 99 (6):e90-3 Haematologica
1592-8721
24633870
10.3324/haematol.2014.104331
http://hdl.handle.net/10033/325037
Haematologica
en
Archived with thanks to Haematologica
Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function.
article2018-06-12T19:59:05Zoai:repository.helmholtz-hzi.de:10033/3326222019-08-30T11:33:05Zcom_10033_620591col_10033_620599
Belikov, Aleksey V
Schraven, Burkhart
Simeoni, Luca
2014-10-09T13:48:19Z
2014-10-09T13:48:19Z
2014
TCR-triggered extracellular superoxide production is not required for T-cell activation. 2014, 12:50 Cell Commun. Signal
1478-811X
25081034
10.1186/s12964-014-0050-1
http://hdl.handle.net/10033/332622
Cell communication and signaling : CCS
In the last decade, reactive oxygen species (ROS) production has been shown to occur upon T-cell receptor (TCR) stimulation and to affect TCR-mediated signalling. However, the exact reactive species that are produced, how ROS are generated and their requirement for T-cell activation, proliferation or cytokine production remain unclear, especially in the case of primary human T cells. Moreover, several groups have questioned that ROS are produced upon TCR stimulation.
en
Archived with thanks to Cell communication and signaling : CCS
TCR-triggered extracellular superoxide production is not required for T-cell activation.
Article2018-06-12T22:35:15ZIn the last decade, reactive oxygen species (ROS) production has been shown to occur upon T-cell receptor (TCR) stimulation and to affect TCR-mediated signalling. However, the exact reactive species that are produced, how ROS are generated and their requirement for T-cell activation, proliferation or cytokine production remain unclear, especially in the case of primary human T cells. Moreover, several groups have questioned that ROS are produced upon TCR stimulation.oai:repository.helmholtz-hzi.de:10033/3462082019-08-30T11:37:23Zcom_10033_620591col_10033_620725
Berod, Luciana
Heinemann, Christina
Heink, Sylvia
Escher, Angelika
Stadelmann, Christine
Drube, Sebastian
Wetzker, Reinhard
Norgauer, Johannes
Kamradt, Thomas
2015-03-05T12:32:37Z
2015-03-05T12:32:37Z
2011-03
PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome. 2011, 41 (3):833-44 Eur. J. Immunol.
1521-4141
21287545
10.1002/eji.201040504
http://hdl.handle.net/10033/346208
European journal of immunology
PI3Ks control signal transduction triggered by growth factors and G-protein-coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kγ in the pathogenesis of EAE. We show that, in the absence of PI3Kγ expression, clinical signs of EAE were delayed and mitigated. PI3Kγ-deficient myelin oligodendrocyte glycoprotein (MOG)(35-55) -specific CD4(+) T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4(+) cells into PI3Kγ(-/-) mice prior to MOG(35-55) immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kγ expression in Th cells for the pathogenesis of EAE; however, PI3Kγ was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kγ(-/-) mice. These findings demonstrate that PI3Kγ contributes to the development of autoimmune CNS inflammation.
en
Adoptive Transfer
Animals
Cell Differentiation
Class Ib Phosphatidylinositol 3-Kinase
Encephalomyelitis, Autoimmune, Experimental
Glycoproteins
Lymphoid Tissue
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
T-Lymphocytes, Helper-Inducer
Time Factors
PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome.
Article2018-06-12T23:02:22ZPI3Ks control signal transduction triggered by growth factors and G-protein-coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kγ in the pathogenesis of EAE. We show that, in the absence of PI3Kγ expression, clinical signs of EAE were delayed and mitigated. PI3Kγ-deficient myelin oligodendrocyte glycoprotein (MOG)(35-55) -specific CD4(+) T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4(+) cells into PI3Kγ(-/-) mice prior to MOG(35-55) immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kγ expression in Th cells for the pathogenesis of EAE; however, PI3Kγ was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kγ(-/-) mice. These findings demonstrate that PI3Kγ contributes to the development of autoimmune CNS inflammation.oai:repository.helmholtz-hzi.de:10033/5567112019-08-30T11:27:46Zcom_10033_620591col_10033_620725
Hurrell, Benjamin P
Schuster, Steffen
Grün, Eva
Coutaz, Manuel
Williams, Roderick A
Held, Werner
Malissen, Bernard
Malissen, Marie
Yousefi, Shida
Simon, Hans-Uwe
Müller, Andreas J
Tacchini-Cottier, Fabienne
Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
2015-06-11T11:40:22Z
2015-06-11T11:40:22Z
2015-05
Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion. 2015, 11 (5):e1004929 PLoS Pathog.
1553-7374
26020515
10.1371/journal.ppat.1004929
http://hdl.handle.net/10033/556711
PLoS pathogens
The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.
en
Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion.
Article2018-06-12T21:42:03ZThe protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.oai:repository.helmholtz-hzi.de:10033/5786252019-08-30T11:29:47Zcom_10033_620591col_10033_620599
Reddycherla, Amarendra V
Meinert, Ines
Reinhold, Annegret
Reinhold, Dirk
Schraven, Burkhart
Simeoni, Luca
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2015-09-23T12:03:29Z
2015-09-23T12:03:29Z
2015
miR-20a inhibits TCR-mediated signaling and cytokine production in human naïve CD4+ T cells. 2015, 10 (4):e0125311 PLoS ONE
1932-6203
25884400
10.1371/journal.pone.0125311
http://hdl.handle.net/10033/578625
PloS one
Upon TCR stimulation by peptide-MHC complexes, CD4+ T cells undergo activation and proliferation. This process will ultimately culminate in T-cell differentiation and the acquisition of effector functions. The production of specific cytokines by differentiated CD4+ T cells is crucial for the generation of the appropriate immune response. Altered CD4+ T-cell activation and cytokine production result in chronic inflammatory conditions and autoimmune disorders. miRNAs have been shown to be important regulators of T-cell biology. In this study, we have focused our investigation on miR-20a, a member of the miR-17-92 cluster, whose expression is decreased in patients suffering from multiple sclerosis. We have found that miR-20a is rapidly induced upon TCR-triggering in primary human naïve CD4+ T cells and that its transcription is regulated in a Erk-, NF-κB-, and Ca++-dependent manner. We have further shown that overexpression of miR-20a inhibits TCR-mediated signaling but not the proliferation of primary human naïve CD4+ T cells. However, miR-20a overexpression strongly suppresses IL-10 secretion and moderately decreases IL-2, IL-6 and IL8 production, which are crucial regulators of inflammatory responses. Our study suggests that miR-20a is a new player in the regulation of TCR signaling strength and cytokine production.
en
miR-20a inhibits TCR-mediated signaling and cytokine production in human naïve CD4+ T cells.
Article2018-06-13T00:39:29ZUpon TCR stimulation by peptide-MHC complexes, CD4+ T cells undergo activation and proliferation. This process will ultimately culminate in T-cell differentiation and the acquisition of effector functions. The production of specific cytokines by differentiated CD4+ T cells is crucial for the generation of the appropriate immune response. Altered CD4+ T-cell activation and cytokine production result in chronic inflammatory conditions and autoimmune disorders. miRNAs have been shown to be important regulators of T-cell biology. In this study, we have focused our investigation on miR-20a, a member of the miR-17-92 cluster, whose expression is decreased in patients suffering from multiple sclerosis. We have found that miR-20a is rapidly induced upon TCR-triggering in primary human naïve CD4+ T cells and that its transcription is regulated in a Erk-, NF-κB-, and Ca++-dependent manner. We have further shown that overexpression of miR-20a inhibits TCR-mediated signaling but not the proliferation of primary human naïve CD4+ T cells. However, miR-20a overexpression strongly suppresses IL-10 secretion and moderately decreases IL-2, IL-6 and IL8 production, which are crucial regulators of inflammatory responses. Our study suggests that miR-20a is a new player in the regulation of TCR signaling strength and cytokine production.oai:repository.helmholtz-hzi.de:10033/5816952019-08-30T11:25:11Zcom_10033_620591col_10033_620599
Mobashir, Mohammad
Madhusudhan, Thati
Isermann, Berend
Beyer, Tilo
Schraven, Burkhart
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2015-11-04T10:51:12Z
2015-11-04T10:51:12Z
2014
Negative interactions and feedback regulations are required for transient cellular response. 2014, 4:3718 Sci Rep
2045-2322
24430195
10.1038/srep03718
http://hdl.handle.net/10033/581695
Scientific reports
Signal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activation nature of downstream signaling molecules. The factors which we have investigated are loops (feed forward and feedback loops), cross-talk of signal transduction pathways, and the change in the concentration of the signaling molecules. Based on our results we conclude that among these factors feedback loop and the cross-talks which directly inhibit the target protein dominantly controls the transient cellular response.
en
Cell Physiological Phenomena
Feedback, Physiological
Models, Biological
Signal Transduction
Negative interactions and feedback regulations are required for transient cellular response.
Article2018-06-13T02:37:26ZSignal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activation nature of downstream signaling molecules. The factors which we have investigated are loops (feed forward and feedback loops), cross-talk of signal transduction pathways, and the change in the concentration of the signaling molecules. Based on our results we conclude that among these factors feedback loop and the cross-talks which directly inhibit the target protein dominantly controls the transient cellular response.oai:repository.helmholtz-hzi.de:10033/5817142019-08-30T11:32:41Zcom_10033_620591col_10033_620599
Simma, Narasimhulu
Bose, Tanima
Kahlfuss, Sascha
Mankiewicz, Judith
Lowinus, Theresa
Lühder, Fred
Schüler, Thomas
Schraven, Burkhart
Heine, Martin
Bommhardt, Ursula
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2015-11-04T12:50:47Z
2015-11-04T12:50:47Z
2014
NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells. 2014, 12:75 Cell Commun. Signal
1478-811X
25477292
10.1186/s12964-014-0075-5
http://hdl.handle.net/10033/581714
Cell communication and signaling : CCS
B cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function.
en
Animals
Antigens, CD40
Apoptosis
B-Lymphocytes
Cell Proliferation
Immunoglobulin G
Immunoglobulin M
Interferon-gamma
Interleukin-10
Intermediate-Conductance Calcium-Activated Potassium Channels
Kv1.3 Potassium Channel
Lipopolysaccharides
Mice, Inbred C57BL
Mice, Transgenic
Piperidines
Receptors, Antigen, B-Cell
Receptors, N-Methyl-D-Aspartate
Toll-Like Receptor 4
NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells.
Article2018-06-13T03:45:56ZB cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function.oai:repository.helmholtz-hzi.de:10033/6011422019-08-30T11:26:12Zcom_10033_620591col_10033_620725
Kurhade, Chaitanya
Zegenhagen, Loreen
Weber, Elvira
Nair, Sharmila
Michaelsen-Preusse, Kristin
Spanier, Julia
Gekara, Nelson O
Kröger, Andrea
Överby, Anna K
Helmholtz Centre for infection research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.
2016-03-10T15:28:49Z
2016-03-10T15:28:49Z
2016
Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1. 2016, 13 (1):22 J Neuroinflammation
1742-2094
26819220
10.1186/s12974-016-0487-9
http://hdl.handle.net/10033/601142
Journal of neuroinflammation
Although type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.
en
Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1.
Article2018-06-12T18:01:17ZAlthough type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.oai:repository.helmholtz-hzi.de:10033/6048452019-08-30T11:24:31Zcom_10033_620591col_10033_620725
Möhle, Luisa
Israel, Nicole
Paarmann, Kristin
Krohn, Markus
Pietkiewicz, Sabine
Müller, Andreas
Lavrik, Inna N
Buguliskis, Jeffrey S
Schott, Björn H
Schlüter, Dirk
Gundelfinger, Eckart D
Montag, Dirk
Seifert, Ulrike
Pahnke, Jens
Dunay, Ildiko Rita
Institute for Medical Microbiology and Hospital Hygiene, University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
2016-04-08T13:39:17Z
2016-04-08T13:39:17Z
2016
Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes. 2016, 4 (1):25 Acta Neuropathol Commun
2051-5960
26984535
10.1186/s40478-016-0293-8
http://hdl.handle.net/10033/604845
Acta neuropathologica communications
Alzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD.
en
Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes.
Article2018-06-13T19:31:50ZAlzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD.oai:repository.helmholtz-hzi.de:10033/6169902019-08-30T11:26:42Zcom_10033_620591col_10033_620599
Cammann, Clemens
Rath, Alexander
Reichl, Udo
Lingel, Holger
Brunner-Weinzierl, Monika
Simeoni, Luca
Schraven, Burkhart
Lindquist, Jonathan A
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-07-15T09:40:17Z
2016-07-15T09:40:17Z
2016
Early changes in the metabolic profile of activated CD8(+) T cells. 2016, 17 (1):28 BMC Cell Biol.
1471-2121
27387758
10.1186/s12860-016-0104-x
http://hdl.handle.net/10033/616990
BMC cell biology
Antigenic stimulation of the T cell receptor (TCR) initiates a change from a resting state into an activated one, which ultimately results in proliferation and the acquisition of effector functions. To accomplish this task, T cells require dramatic changes in metabolism. Therefore, we investigated changes of metabolic intermediates indicating for crucial metabolic pathways reflecting the status of T cells. Moreover we analyzed possible regulatory molecules required for the initiation of the metabolic changes.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Early changes in the metabolic profile of activated CD8(+) T cells.
Article2018-06-12T23:51:17ZAntigenic stimulation of the T cell receptor (TCR) initiates a change from a resting state into an activated one, which ultimately results in proliferation and the acquisition of effector functions. To accomplish this task, T cells require dramatic changes in metabolism. Therefore, we investigated changes of metabolic intermediates indicating for crucial metabolic pathways reflecting the status of T cells. Moreover we analyzed possible regulatory molecules required for the initiation of the metabolic changes.oai:repository.helmholtz-hzi.de:10033/6205682019-08-30T11:26:42Zcom_10033_620591col_10033_620599
Lowinus, Theresa
Bose, Tanima
Busse, Stefan
Busse, Mandy
Reinhold, Dirk
Schraven, Burkhart
Bommhardt, Ursula H H
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-11-04T10:28:09Z
2016-11-04T10:28:09Z
2016-07-22
Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness. 2016 Oncotarget
1949-2553
27462773
10.18632/oncotarget.10777
http://hdl.handle.net/10033/620568
Oncotarget
Memantine is approved for the treatment of advanced Alzheimer´s disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D-aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3-antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors. Concurrent with the in vitro data, CD4+ T cells from AD patients receiving therapeutic doses of memantine show a transient decline of Kv1.3 channel activity and a long-lasting reduced proliferative response to alloantigens in mixed lymphocyte reactions. Furthermore, memantine treatment provokes a profound depletion of peripheral blood memory CD45RO+ CD4+ T cells. Thus, standard doses of memantine profoundly reduce T cell responses in treated patients through blockade of Kv1.3 channels. This may normalize deviant immunopathology in AD and contribute to the beneficial effects of memantine, but may also account for the enhanced infection rate.
ENG
http://creativecommons.org/licenses/by-nc-sa/4.0/
Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness.
Article2018-06-12T23:49:02ZMemantine is approved for the treatment of advanced Alzheimer´s disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D-aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3-antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors. Concurrent with the in vitro data, CD4+ T cells from AD patients receiving therapeutic doses of memantine show a transient decline of Kv1.3 channel activity and a long-lasting reduced proliferative response to alloantigens in mixed lymphocyte reactions. Furthermore, memantine treatment provokes a profound depletion of peripheral blood memory CD45RO+ CD4+ T cells. Thus, standard doses of memantine profoundly reduce T cell responses in treated patients through blockade of Kv1.3 channels. This may normalize deviant immunopathology in AD and contribute to the beneficial effects of memantine, but may also account for the enhanced infection rate.oai:repository.helmholtz-hzi.de:10033/6206092019-08-30T11:35:13Zcom_10033_620591col_10033_620725
Lindqvist, Richard
Mundt, Filip
Gilthorpe, Jonathan D
Wölfel, Silke
Gekara, Nelson O
Kröger, Andrea
Överby, Anna K
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-11-30T14:43:27Z
2016-11-30T14:43:27Z
2016-10-24
Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. 2016, 13 (1):277 J Neuroinflammation
1742-2094
27776548
10.1186/s12974-016-0748-7
http://hdl.handle.net/10033/620609
Journal of neuroinflammation
Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined.
ENG
http://creativecommons.org/licenses/by-nc-sa/4.0/
Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects.
Article2018-06-13T03:57:02ZNeurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined.oai:repository.helmholtz-hzi.de:10033/6208372019-08-30T11:36:33Zcom_10033_620591col_10033_620725
Witte, Amelie
Meineke, Bernhard
Sticht, Jana
Philipsen, Lars
Kuropka, Benno
Müller, Andreas J
Freund, Christian
Schraven, Burkhart
Kliche, Stefanie
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-02-22T15:22:27Z
2017-02-22T15:22:27Z
2017-01-04
D120 and K152 within the PH domain of T cell adapter SKAP55 regulate plasma membrane targeting of SKAP55 and LFA-1 affinity modulation in human T lymphocytes. 2017 Mol. Cell. Biol.
1098-5549
28052935
10.1128/MCB.00509-16
http://hdl.handle.net/10033/620837
Molecular and cellular biology
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its Pleckstrin Homology (PH) domain. We identified two critical amino acid residues within the PH domain of SKAP55, aspartic acid 120 (D120) and lysine 152 (K152). D120 facilitates retention of SKAP55 in the cytoplasm of non-stimulated T cells while K152 promotes SKAP55 membrane recruitment via Actin binding upon TCR-triggering. Importantly, the K152-dependent interaction of the PH domain with Actin promotes the binding of Talin to LFA-1 thus facilitating LFA-1 activation. These data suggest that K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
D120 and K152 within the PH domain of T cell adapter SKAP55 regulate plasma membrane targeting of SKAP55 and LFA-1 affinity modulation in human T lymphocytes.
Article2017-07-04T00:00:00ZThe β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its Pleckstrin Homology (PH) domain. We identified two critical amino acid residues within the PH domain of SKAP55, aspartic acid 120 (D120) and lysine 152 (K152). D120 facilitates retention of SKAP55 in the cytoplasm of non-stimulated T cells while K152 promotes SKAP55 membrane recruitment via Actin binding upon TCR-triggering. Importantly, the K152-dependent interaction of the PH domain with Actin promotes the binding of Talin to LFA-1 thus facilitating LFA-1 activation. These data suggest that K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1.oai:repository.helmholtz-hzi.de:10033/6210642019-08-30T11:37:44Zcom_10033_620591col_10033_620599
Raza, Syed Ahsan
Albrecht, Anne
Çalışkan, Gürsel
Müller, Bettina
Demiray, Yunus Emre
Ludewig, Susann
Meis, Susanne
Faber, Nicolai
Hartig, Roland
Schraven, Burkhart
Lessmann, Volkmar
Schwegler, Herbert
Stork, Oliver
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-17T13:26:03Z
2017-08-17T13:26:03Z
2017-08-04
HIPP neurons in the dentate gyrus mediate the cholinergic modulation of background context memory salience. 2017, 8 (1):189 Nat Commun
2041-1723
28775269
10.1038/s41467-017-00205-3
http://hdl.handle.net/10033/621064
Nature communications
Cholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST(+) interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY(+) hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
HIPP neurons in the dentate gyrus mediate the cholinergic modulation of background context memory salience.
Article2018-06-13T01:08:41ZCholinergic neuromodulation in the hippocampus controls the salience of background context memory acquired in the presence of elemental stimuli predicting an aversive reinforcement. With pharmacogenetic inhibition we here demonstrate that hilar perforant path-associated (HIPP) cells of the dentate gyrus mediate the devaluation of background context memory during Pavlovian fear conditioning. The salience adjustment is sensitive to reduction of hilar neuropeptide Y (NPY) expression via dominant negative CREB expression in HIPP cells and to acute blockage of NPY-Y1 receptors in the dentate gyrus during conditioning. We show that NPY transmission and HIPP cell activity contribute to inhibitory effects of acetylcholine in the dentate gyrus and that M1 muscarinic receptors mediate the cholinergic activation of HIPP cells as well as their control of background context salience. Our data provide evidence for a peptidergic local circuit in the dentate gyrus that mediates the cholinergic encoding of background context salience during fear memory acquisition.Intra-hippocampal circuits are essential for associating a background context with behaviorally salient stimuli and involve cholinergic modulation at SST(+) interneurons. Here the authors show that the salience of the background context memory is modulated through muscarinic activation of NPY(+) hilar perforant path associated interneurons and NPY signaling in the dentate gyrus.oai:repository.helmholtz-hzi.de:10033/6210802019-08-30T11:26:13Zcom_10033_338554com_10033_620591col_10033_621050col_10033_620599
Thurm, Christoph
Poltorak, Mateusz P
Reimer, Elisa
Brinkmann, Melanie M
Leichert, Lars
Schraven, Burkhart
Simeoni, Luca
Helmholtz Centre of infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-30T11:18:03Z
2017-08-30T11:18:03Z
2017-05-09
A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity. 2017, 8 (19):30805-30816 Oncotarget
1949-2553
28415650
10.18632/oncotarget.16486
http://hdl.handle.net/10033/621080
Oncotarget
ζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines. Here, we have investigated whether also oxidation of cysteine residues regulates Zap70 functions. We have identified C575 as a major sulfenylation site of Zap70. A C575A substitution results in protein instability, reduced activity, and increased dependency on the Hsp90/Cdc37 chaperone system. Indeed, Cdc37 overexpression reconstituted partially the expression but fully the function of Zap70C575A. C575 lies within a Mx(2)CWx(6)R motif which is highly conserved among almost all human tyrosine kinases. Mutation of any of the conserved amino acids, but not of a non-conserved residue preceding the cysteine, also results in Zap70 instability. Collectively, we have identified a new redox-active motif which is crucial for the regulation of Zap70 stability/activity. We believe that this motif has the potential to become a novel target for the development of therapeutic tools to modulate the expression/activity of kinases.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity.
Article2018-06-13T05:25:16Zζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines. Here, we have investigated whether also oxidation of cysteine residues regulates Zap70 functions. We have identified C575 as a major sulfenylation site of Zap70. A C575A substitution results in protein instability, reduced activity, and increased dependency on the Hsp90/Cdc37 chaperone system. Indeed, Cdc37 overexpression reconstituted partially the expression but fully the function of Zap70C575A. C575 lies within a Mx(2)CWx(6)R motif which is highly conserved among almost all human tyrosine kinases. Mutation of any of the conserved amino acids, but not of a non-conserved residue preceding the cysteine, also results in Zap70 instability. Collectively, we have identified a new redox-active motif which is crucial for the regulation of Zap70 stability/activity. We believe that this motif has the potential to become a novel target for the development of therapeutic tools to modulate the expression/activity of kinases.oai:repository.helmholtz-hzi.de:10033/6210822019-08-30T11:36:33Zcom_10033_128109com_10033_620591col_10033_128110col_10033_620599
Ranjan, Satish
Goihl, Alexander
Kohli, Shrey
Gadi, Ihsan
Pierau, Mandy
Shahzad, Khurrum
Gupta, Dheerendra
Bock, Fabian
Wang, Hongjie
Shaikh, Haroon
Kähne, Thilo
Reinhold, Dirk
Bank, Ute
Zenclussen, Ana C
Niemz, Jana
Schnöder, Tina M
Brunner-Weinzierl, Monika
Fischer, Thomas
Kalinski, Thomas
Schraven, Burkhart
Luft, Thomas
Huehn, Jochen
Naumann, Michael
Heidel, Florian H
Isermann, Berend
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-31T13:10:31Z
2017-08-31T13:10:31Z
2017-08-21
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat Commun
2041-1723
28827518
10.1038/s41467-017-00169-4
http://hdl.handle.net/10033/621082
Nature communications
Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
Article2018-06-12T23:27:54ZGraft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.oai:repository.helmholtz-hzi.de:10033/6211262019-08-30T11:32:17Zcom_10033_620591com_10033_128109com_10033_311308col_10033_620725col_10033_128110col_10033_620721
van Ham, Marco
Teich, René
Philipsen, Lars
Niemz, Jana
Amsberg, Nicole
Wissing, Josef
Nimtz, Manfred
Gröbe, Lothar
Kliche, Stefanie
Thiel, Nadine
Klawonn, Frank
Hubo, Mario
Jonuleit, Helmut
Reichardt, Peter
Müller, Andreas J
Huehn, Jochen
Jänsch, Lothar
Helmholtz-Zetrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-09-28T12:14:50Z
2017-09-28T12:14:50Z
2017-08-17
TCR signalling network organization at the immunological synapses of murine regulatory T cells. 2017 Eur. J. Immunol.
1521-4141
28833060
10.1002/eji.201747041
http://hdl.handle.net/10033/621126
European journal of immunology
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCθ, PLCγ1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
TCR signalling network organization at the immunological synapses of murine regulatory T cells.
Article2018-06-13T21:23:07ZRegulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCθ, PLCγ1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells.oai:repository.helmholtz-hzi.de:10033/6212162021-07-06T12:05:05Zcom_10033_620652com_10033_620601com_10033_620591com_10033_622921col_10033_620725col_10033_620666col_10033_622926col_10033_620602
Volckmar, Julia
Gereke, Marcus
Ebensen, Thomas
Riese, Peggy
Philipsen, Lars
Lienenklaus, Stefan
Wohlleber, Dirk
Klopfleisch, Robert
Stegemann-Koniszewski, Sabine
Müller, Andreas J
Gruber, Achim D
Knolle, Percy
Guzman, Carlos A
Bruder, Dunja
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-01-02T13:05:22Z
2018-01-02T13:05:22Z
2017-03-07
Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver. 2017, 7:43985 Sci Rep
2045-2322
28266658
10.1038/srep43985
http://hdl.handle.net/10033/621216
Scientific reports
Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Targeted antigen delivery to dendritic cells elicits robust antiviral T cell-mediated immunity in the liver.
Article2018-06-02T16:00:45ZHepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.oai:repository.helmholtz-hzi.de:10033/6213712019-08-30T11:30:58Zcom_10033_620591col_10033_620725
Neumann, Jens
Henneberg, Sophie
von Kenne, Susanne
Nolte, Niklas
Müller, Andreas J
Schraven, Burkhart
Görtler, Michael W
Reymann, Klaus G
Gunzer, Matthias
Riek-Burchardt, Monika
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-05-14T14:34:02Z
2018-05-14T14:34:02Z
2018
Beware the intruder: Real time observation of infiltrated neutrophils and neutrophil-Microglia interaction during stroke in vivo. 2018, 13 (3):e0193970 PLoS ONE
1932-6203
29543836
10.1371/journal.pone.0193970
http://hdl.handle.net/10033/621371
PloS one
Inflammation plays an important role in the pathogenesis of ischemic stroke including an acute and prolonged inflammatory process. The role of neutrophil granulocytes as first driver of the immune reaction from the blood site is under debate due to controversial findings. In bone marrow chimeric mice we were able to study the dynamics of tdTomato-expressing neutrophils and GFP-expressing microglia after photothrombosis using intravital two-photon microscopy. We demonstrate the infiltration of neutrophils into the brain parenchyma and confirm a long-lasting contact between neutrophils and microglia as well as an uptake of neutrophils by microglia clearing the brain from peripheral immune cells.
en
Beware the intruder: Real time observation of infiltrated neutrophils and neutrophil-Microglia interaction during stroke in vivo.
Article2018-06-13T21:39:21ZInflammation plays an important role in the pathogenesis of ischemic stroke including an acute and prolonged inflammatory process. The role of neutrophil granulocytes as first driver of the immune reaction from the blood site is under debate due to controversial findings. In bone marrow chimeric mice we were able to study the dynamics of tdTomato-expressing neutrophils and GFP-expressing microglia after photothrombosis using intravital two-photon microscopy. We demonstrate the infiltration of neutrophils into the brain parenchyma and confirm a long-lasting contact between neutrophils and microglia as well as an uptake of neutrophils by microglia clearing the brain from peripheral immune cells.oai:repository.helmholtz-hzi.de:10033/6215402019-08-30T11:29:41Zcom_10033_620591col_10033_620725
Edelmann, Bärbel
Gupta, Nibedita
Schnoeder, Tina M
Oelschlegel, Anja M
Shahzad, Khurrum
Goldschmidt, Jürgen
Philipsen, Lars
Weinert, Soenke
Ghosh, Aniket
Saalfeld, Felix C
Nimmagadda, Subbaiah Chary
Müller, Peter
Braun-Dullaeus, Rüdiger
Mohr, Juliane
Wolleschak, Denise
Kliche, Stefanie
Amthauer, Holger
Heidel, Florian H
Schraven, Burkhart
Isermann, Berend
Müller, Andreas J
Fischer, Thomas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-11-06T14:53:19Z
2018-11-06T14:53:19Z
2018-10-01
1558-8238
30024857
10.1172/JCI90312
http://hdl.handle.net/10033/621540
JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Hematology
Integrins
Thrombosis
JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation.
Article
The Journal of clinical investigation2018-11-06T14:53:19Zoai:repository.helmholtz-hzi.de:10033/6216272019-08-30T11:29:42Zcom_10033_620591col_10033_620725
Heyde, Sandrina
Philipsen, Lars
Formaglio, Pauline
Fu, Yan
Baars, Iris
Höbbel, Guido
Kleinholz, Corinna L
Seiß, Elena A
Stettin, Juliane
Gintschel, Patricia
Dudeck, Anne
Bousso, Philippe
Schraven, Burkhart
Müller, Andreas J
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-01-02T15:21:32Z
2019-01-02T15:21:32Z
2018-10-01
1553-7374
30346994
10.1371/journal.ppat.1007374
http://hdl.handle.net/10033/621627
The virulence of intracellular pathogens such as Leishmania major (L. major) relies largely on their ability to undergo cycles of replication within phagocytes, release, and uptake into new host cells. While all these steps are critical for successful establishment of infection, neither the cellular niche of efficient proliferation, nor the spread to new host cells have been characterized in vivo. Here, using a biosensor for measuring pathogen proliferation in the living tissue, we found that monocyte-derived Ly6C+CCR2+ phagocytes expressing CD11c constituted the main cell type harboring rapidly proliferating L. major in the ongoing infection. Synchronization of host cell recruitment and intravital 2-photon imaging showed that these high proliferating parasites preferentially underwent cell-to-cell spread. However, newly recruited host cells were infected irrespectively of their cell type or maturation state. We propose that among these cells, CD11c-expressing monocytes are most permissive for pathogen proliferation, and thus mainly fuel the cycle of intracellular proliferation and cell-to-cell transfer during the acute infection. Thus, besides the well-described function for priming and activating T cell effector functions against L. major, CD11c-expressing monocyte-derived cells provide a reservoir for rapidly proliferating parasites that disseminate at the site of infection.
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
CD11c-expressing Ly6C+CCR2+ monocytes constitute a reservoir for efficient Leishmania proliferation and cell-to-cell transmission.
Article
PLoS pathogens2019-01-02T15:21:33Zoai:repository.helmholtz-hzi.de:10033/6215622019-08-30T11:27:40Zcom_10033_620591col_10033_620725col_10033_620599
Heyde, Sandrina
Philipsen, Lars
Formaglio, Pauline
Fu, Yan
Baars, Iris
Höbbel, Guido
Kleinholz, Corinna L
Seiß, Elena A
Stettin, Juliane
Gintschel, Patricia
Dudeck, Anne
Bousso, Philippe
Schraven, Burkhart
Müller, Andreas J
2018-11-14T10:06:37Z
2018-11-14T10:06:37Z
2018-10-01
1553-7374
30346994
10.1371/journal.ppat.1007374
http://hdl.handle.net/10033/621562
The virulence of intracellular pathogens such as Leishmania major (L. major) relies largely on their ability to undergo cycles of replication within phagocytes, release, and uptake into new host cells. While all these steps are critical for successful establishment of infection, neither the cellular niche of efficient proliferation, nor the spread to new host cells have been characterized in vivo. Here, using a biosensor for measuring pathogen proliferation in the living tissue, we found that monocyte-derived Ly6C+CCR2+ phagocytes expressing CD11c constituted the main cell type harboring rapidly proliferating L. major in the ongoing infection. Synchronization of host cell recruitment and intravital 2-photon imaging showed that these high proliferating parasites preferentially underwent cell-to-cell spread. However, newly recruited host cells were infected irrespectively of their cell type or maturation state. We propose that among these cells, CD11c-expressing monocytes are most permissive for pathogen proliferation, and thus mainly fuel the cycle of intracellular proliferation and cell-to-cell transfer during the acute infection. Thus, besides the well-described function for priming and activating T cell effector functions against L. major, CD11c-expressing monocyte-derived cells provide a reservoir for rapidly proliferating parasites that disseminate at the site of infection.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
CD11c-expressing Ly6C+CCR2+ monocytes constitute a reservoir for efficient Leishmania proliferation and cell-to-cell transmission.
Article
PLoS pathogens2018-11-14T10:06:37Zoai:repository.helmholtz-hzi.de:10033/6216492019-01-16T01:24:01Zcom_10033_620591col_10033_620725col_10033_620599
Waldt, Natalie
Seifert, Anke
Demiray, Yunus Emre
Devroe, Eric
Turk, Benjamin E
Reichardt, Peter
Mix, Charlie
Reinhold, Annegret
Freund, Christian
Müller, Andreas J
Schraven, Burkhart
Stork, Oliver
Kliche, Stefanie
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-01-15T14:01:20Z
2019-01-15T14:01:20Z
2018-01-01
Front Immunol. 2018 Dec 4;9:2852. doi: 10.3389/fimmu.2018.02852. eCollection 2018.
1664-3224
30568657
10.3389/fimmu.2018.02852
http://hdl.handle.net/10033/621649
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Filamin A
Kindlin-3
LFA-1
Ndr2
T cells
TCR
Talin
inside-out signaling
Filamin A Phosphorylation at Serine 2152 by the Serine/Threonine Kinase Ndr2 Controls TCR-Induced LFA-1 Activation in T Cells.
Article
Frontiers in immunology2019-01-15T14:01:20Zoai:repository.helmholtz-hzi.de:10033/6216902019-08-30T11:32:39Zcom_10033_620591com_10033_128109col_10033_621829col_10033_620599
Lowinus, Theresa
Heidel, Florian H
Bose, Tanima
Nimmagadda, Subbaiah Chary
Schnöder, Tina
Cammann, Clemens
Schmitz, Ingo
Seifert, Ulrike
Fischer, Thomas
Schraven, Burkhart
Bommhardt, Ursula
2019-02-15T12:47:18Z
2019-02-15T12:47:18Z
2019-01-16
1478-811X
30651113
10.1186/s12964-018-0317-z
http://hdl.handle.net/10033/621690
Cell Communication and Signaling
Treatment of acute leukemia is challenging and long-lasting remissions are difficult to induce. Innovative therapy approaches aim to complement standard chemotherapy to improve drug efficacy and decrease toxicity. Promising new therapeutic targets in cancer therapy include voltage-gated K We analyzed acute lymphoid (Jurkat, CEM) and myeloid (HL-60, Molm-13, OCI-AML-3) leukemia cell lines and patients' acute leukemic blasts after treatment with either drug alone or the combination of cytarabine and memantine. Patch-clamp analysis was performed to evaluate inhibition of K Our study demonstrates that memantine inhibits K Our study underlines inhibition of K
en
BMC
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Acute leukemia
Cell death
Cytarabine
Memantine
Signaling
Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of K1.3 potassium channels, AKT and ERK1/2 signaling.
Article
Cell communication and signaling : CCS2019-02-15T12:47:19Zoai:repository.helmholtz-hzi.de:10033/6217382019-08-30T11:30:26Zcom_10033_620591col_10033_620599
Rudolph, Jochen Michael
Guttek, Karina
Weitz, Gabriele
Meinke, Clara Antonia
Kliche, Stefanie
Reinhold, Dirk
Schraven, Burkhart
Reinhold, Annegret
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
2019-04-04T09:49:22Z
2019-04-04T09:49:22Z
2019-03-04
1098-5549
30833485
10.1128/MCB.00365-18
http://hdl.handle.net/10033/621738
Molecular and Cellular Biology
The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knock-out mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knock-out mice (ADAPfl/fl PF4-Cretg). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even after stimulation conditions. ADAPfl/fl PF4-Cretg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and TGF-β1. In vitro, platelets from these mice revealed reduced P-selectin expression, lower TGF-β1 release, diminished integrin αIIbβ3 activation and decreased fibrinogen binding after stimulation with podoplanin, the ligand of the C-type lectin-like receptor-2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of PLCγ2 and Erk1/2. Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-β1 early after T cell transfer improved EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.
en
ASM
https://mcb.asm.org/content/early/2019/03/01/MCB.00365-18.long
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Characterization of mice with a platelet-specific deletion of the adapter molecule ADAP.
Article
Molecular and cellular biology
oai:repository.helmholtz-hzi.de:10033/6217722019-08-30T11:24:25Zcom_10033_620591com_10033_128109col_10033_621771col_10033_620599
Waldt, Natalie
Seifert, Anke
Demiray, Yunus Emre
Devroe, Eric
Turk, Benjamin E
Reichardt, Peter
Mix, Charlie
Reinhold, Annegret
Freund, Christian
Müller, Andreas J
Schraven, Burkhart
Stork, Oliver
Kliche, Stefanie
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
2019-05-13T14:16:36Z
2019-05-13T14:16:36Z
2018-01-01
Front Immunol. 2018 Dec 4;9:2852. doi: 10.3389/fimmu.2018.02852. eCollection 2018.
1664-3224
30568657
10.3389/fimmu.2018.02852
http://hdl.handle.net/10033/621772
Frontiers in immunology
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Filamin A
Kindlin-3
LFA-1
Ndr2
T cells
TCR
Talin
inside-out signaling
Filamin A Phosphorylation at Serine 2152 by the Serine/Threonine Kinase Ndr2 Controls TCR-Induced LFA-1 Activation in T Cells.
Article
Frontiers in immunology2019-05-13T14:16:36Zoai:repository.helmholtz-hzi.de:10033/6218062019-08-30T11:28:19Zcom_10033_620591com_10033_128109com_10033_620618col_10033_621771col_10033_620599col_10033_620621
Seiß, Elena A
Krone, Anna
Formaglio, Pauline
Goldmann, Oliver
Engelmann, Susanne
Schraven, Burkhart
Medina, Eva
Müller, Andreas J
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-06-07T12:34:07Z
2019-06-07T12:34:07Z
2019-04-05
Sci Rep. 2019 Apr 5;9(1):5703. doi: 10.1038/s41598-019-42129-6.
2045-2322
30952906
10.1038/s41598-019-42129-6
http://hdl.handle.net/10033/621806
Scientific Reports
Upon the onset of inflammatory responses, bacterial pathogens are confronted with altered tissue microenvironments which can critically impact on their metabolic activity and growth. Changes in these parameters have however remained difficult to analyze over time, which would be critical to dissect the interplay between the host immune response and pathogen physiology. Here, we established an in vivo biosensor for measuring the growth rates of Staphylococcus aureus (S. aureus) on a single cell-level over days in an ongoing cutaneous infection. Using intravital 2-photon imaging and quantitative fluorescence microscopy, we show that upon neutrophil recruitment to the infection site and bacterial uptake, non-lethal dampening of S. aureus proliferation occurred. This inhibition was supported by NADPH oxidase activity. Therefore, reactive oxygen production contributes to pathogen containment within neutrophils not only by killing S. aureus, but also by restricting the growth rate of the bacterium.
Nature publishing group
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Longitudinal proliferation mapping in vivo reveals NADPH oxidase-mediated dampening of Staphylococcus aureus growth rates within neutrophils.
Article
Scientific reports2019-06-07T12:34:08Zoai:repository.helmholtz-hzi.de:10033/6219702021-07-05T15:12:59Zcom_10033_620652com_10033_620591com_10033_622921col_10033_622922col_10033_620666col_10033_620724
Zheng, Xiaoyan
Oduro, Jennifer D
Boehme, Julia D
Borkner, Lisa
Ebensen, Thomas
Heise, Ulrike
Gereke, Marcus
Pils, Marina C
Krmpotic, Astrid
Guzmán, Carlos A
Bruder, Dunja
Čičin-Šain, Luka
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-10-09T11:14:24Z
2019-10-09T11:14:24Z
2019-09-01
PLoS Pathog. 2019 Sep 16;15(9):e1008036. doi: 10.1371/journal.ppat.1008036. eCollection 2019 Sep.
1553-7374
31525249
10.1371/journal.ppat.1008036
http://hdl.handle.net/10033/621970
PLOS pathogens
Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.
en
PLOS
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge.
Article
PLoS pathogens2019-10-09T11:14:25Zoai:repository.helmholtz-hzi.de:10033/6221712020-12-01T14:30:26Zcom_10033_620652com_10033_311308com_10033_620591col_10033_620666col_10033_620724col_10033_620721
Böning, Martha A L
Trittel, Stephanie
Riese, Peggy
van Ham, Marco
Heyner, Maxi
Voss, Martin
Parzmair, Gerald P
Klawonn, Frank
Jeron, Andreas
Guzman, Carlos A
Jänsch, Lothar
Schraven, Burkhart
Reinhold, Annegret
Bruder, Dunja
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-02-26T08:58:18Z
2020-02-26T08:58:18Z
2019-01-01
Front Immunol. 2020 Jan 22;10:3144. doi: 10.3389/fimmu.2019.03144. eCollection 2019.
1664-3224
32038647
10.3389/fimmu.2019.03144
http://hdl.handle.net/10033/622171
Frontiers of Immunology
The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date only limited and moreover conflicting data exist regarding the role of ADAP in NK cells. To extend existing knowledge we investigated ADAP-dependency of NK cells in the context of in vivo infection with the intracellular pathogen Listeria monocytogenes (Lm). Ex vivo analysis of infection-primed NK cells revealed impaired cytotoxic capacity in NK cells lacking ADAP as indicated by reduced CD107a surface expression and inefficient perforin production. However, ADAP-deficiency had no global effect on NK cell morphology or intracellular distribution of CD107a-containing vesicles. Proteomic definition of ADAPko and wild type NK cells did not uncover obvious differences in protein composition during the steady state and moreover, similar early response patterns were induced in NK cells upon infection independent of the genotype. In line with protein network analyses that suggested an altered migration phenotype in naïve ADAPko NK cells, in vitro migration assays uncovered significantly reduced migration of both naïve as well as infection-primed ADAPko NK cells compared to wild type NK cells. Notably, this migration defect was associated with a significantly reduced expression of the integrin CD11a on the surface of splenic ADAP-deficient NK cells 1 day post-Lm infection. We propose that ADAP-dependent alterations in integrin expression might account at least in part for the fact that during in vivo infection significantly lower numbers of ADAPko NK cells accumulate in the spleen i.e., the site of infection. In conclusion, we show here that during systemic Lm infection in mice ADAP is essential for efficient cytotoxic capacity and migration of NK cells.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
ADAP
CD11a
IL-10
Listeria monocytogenes
cytotoxicity
in vivo infection
migration
natural killer cells
ADAP Promotes Degranulation and Migration of NK Cells Primed During vivo Listeria monocytogenes Infection in Mice.
Article
Frontiers in immunology2020-02-26T08:58:19Zoai:repository.helmholtz-hzi.de:10033/6223422020-07-03T01:31:20Zcom_10033_620591col_10033_620724
Veluswamy, Priya
Bruder, Dunja
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-07-02T13:11:02Z
2020-07-02T13:11:02Z
2018-04
2218-676X
10.21037/tcr.2018.04.04
http://hdl.handle.net/10033/622342
2219-6803
Translational Cancer Research
T cell exhaustion is a well-known mechanism involved in escape of degenerated cells or certain pathogens from CD8+ T cell-mediated immune surveillance, ultimately resulting in tumor development and chronic infections, respectively. Next to activated T cells, exhausted CD8+ T cells typically express high levels of the programmed cell death-1 (PD-1) receptor. While interaction of PD-1 with its ligand programmed death-ligand 1 (PD-L1) on hemotopoietic and non-hemotopoietic cells is important for the re-establishment of homeostasis following immune activation, PD-1/PD-L1 interaction represents a major drawback in certain other disease settings such as cancer or chronic viral infections. Here PD-1 signalling in T cells prevents efficient anti-tumor or anti-viral immune responses. Thus, therapeutic interference with the PD-1/PD-L1 pathway represents a promising approach for releasing exhausted CD8+ T cells from PD-1-dependent suppression and reactivation of effector functions. However, recent reports have highlighted unexpected outcomes of PD-1/PD-L1 pathway inhibition in the context of chronic infections. We provide here a comprehensive overview of the recent discoveries made in the context of PD-1/PD-L1 checkpoint inhibition that are considered relevant with respect to the targeted reactivation of effector functions in exhausted CD8+ T cells. We briefly discuss the impact of PD-1 signalling on the expression of certain transcription factors, on epigenetic modifications affecting chromatin accessibility, on cellular metabolism and the expression of certain cytokine receptors involved in immune homeostasis. These newly uncovered facts should be carefully considered before further development of therapies targeting the PD-1/PD-L1 pathway that are aiming at the restoration of pathogen-specific and anti-tumor CD8+ T cell effector functions in order to prevent adverse side effects. © 2018, Translational Cancer Research.
en
AME Publishing Company
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
PD-1/PD-L1 pathway inhibition to restore effector functions in exhausted CD8+ T cells: chances, limitations and potential risks
Article
7
S4
S530
S537
Translational Cancer Research2020-07-02T13:11:04Zoai:repository.helmholtz-hzi.de:10033/6223432020-07-08T03:31:26Zcom_10033_620591com_10033_620652col_10033_620666col_10033_620724
Stegemann-Koniszewski, Sabine
Behrens, Sarah
Boehme, Julia D
Hochnadel, Inga
Riese, Peggy
Guzmán, Carlos A
Kröger, Andrea
Schreiber, Jens
Gunzer, Matthias
Bruder, Dunja
ZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-07-07T11:37:39Z
2020-07-07T11:37:39Z
2018-02-13
Front Immunol. 2018;9:245. Published 2018 Feb 13. doi:10.3389/fimmu.2018.00245.
1664-3224
29497422
10.3389/fimmu.2018.00245
http://hdl.handle.net/10033/622343
Frontiers in immunology
The innate immune system senses influenza A virus (IAV) through different pathogen-recognition receptors including Toll-like receptor 7 (TLR7). Downstream of viral recognition natural killer (NK) cells are activated as part of the anti-IAV immune response. Despite the known decisive role of TLR7 for NK cell activation by therapeutic immunostimulatory RNAs, the contribution of TLR7 to the NK cell response following IAV infection has not been addressed. We have analyzed lung cytokine responses as well as the activation, interferon (IFN)-γ production, and cytotoxicity of lung and splenic NK cells following sublethal respiratory IAV infection in wild-type and TLR7ko mice. Early airway IFN-γ levels as well as the induction of lung NK cell CD69 expression and IFN-γ production in response to IAV infection were significantly attenuated in TLR7-deficient hosts. Strikingly, respiratory IAV infection also primed splenic NK cells for IFN-γ production, degranulation, and target cell lysis, all of which were fully dependent on TLR7. At the same time, lung type I IFN levels were significantly reduced in TLR7ko mice early following IAV infection, displaying a potential upstream mechanism of the attenuated NK cell activation observed. Taken together, our data clearly demonstrate a specific role for TLR7 signaling in local and systemic NK cell activation following respiratory IAV infection despite the presence of redundant innate IAV-recognition pathways.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Toll-like receptor 7
influenza A virus
innate immunity
natural killer cells
pathogen-recognition receptors
respiratory infection
Respiratory Influenza A Virus Infection Triggers Local and Systemic Natural Killer Cell Activation Toll-Like Receptor 7.
Article
Other
9
245
Frontiers in immunology
Switzerland2020-07-07T11:37:40Zoai:repository.helmholtz-hzi.de:10033/6226242020-12-08T01:48:09Zcom_10033_620591col_10033_620724
Ogger, Patricia P.
Silva, Johnatas Dutra
Aghapour, Mahyar
Persson, Irma Mahmutovic
Tulen, Christy
Jurkowska, Renata
Ubags, Niki D.
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-11-30T16:07:52Z
2020-11-30T16:07:52Z
2020-09-01
Breathe, 16(3), 1-8. doi:10.1183/20734735.0063-2020.
18106838
10.1183/20734735.0063-2020
http://hdl.handle.net/10033/622624
20734735
Breathe
2-s2.0-85094577229
SCOPUS_ID:85094577229
Every year, the European Respiratory Society (ERS) organises the Lung Science Conference (LSC) in Estoril, Portugal, to discuss basic and translational science. The topic of the LSC 2020 was “Metabolic alterations in lung ageing and disease”. In addition to an outstanding scientific programme, the LSC provides excellent opportunities for career development and inclusion of Early Career Members (ECMs). All scientific and poster sessions are chaired by an ECM who is paired with a senior faculty member to allow ECMs to become acquainted with session chairing. In addition, 40 travel bursaries are made available to abstract authors and all bursary recipients are invited to take part in a mentorship lunch. Moreover, there is a session organised by the Early Career Members Committee (ECMC) dedicated to career development. Here, we describe the scientific highlights of LSC 2020 for those who could not attend. The ERS presents several awards at the LSC and here we will highlight all winners of the LSC 2020 awards. The five highest ranked abstracts from ECMs are presented during the Young investigator session. Patricia Ogger (UK) was presented with the William MacNee Award for the best presentation in this session. Several abstracts were selected for programmed oral presentations and Renata Jurkowska (UK) was presented with the inaugural Geoffrey Laurent Award for the best oral presentation. Moreover, the organisers presented eight Distinguished Poster awards to Anne-Sophie Lamort (Germany), Julia Frankenberg Garcia (UK), Johnatas Silva (UK), Pauline Esteves (France), Claudio Bussi (UK), Elodie Picard (France), Felix Ritzmann (Germany) and Alen Faiz (Australia) for their excellent contributions during the poster session.
European Commission
European Respiratory Society
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Early career members at the ers lung science conference 2020: Metabolic alterations in lung ageing and disease
Article
16
3
1
8
Breathe2020-11-30T16:07:53Zoai:repository.helmholtz-hzi.de:10033/6226612021-01-06T01:33:40Zcom_10033_620591col_10033_620724
Wu, Qingyu
Jorde, Ilka
Kershaw, Olivia
Jeron, Andreas
Bruder, Dunja
Schreiber, Jens
Stegemann-Koniszewski, Sabine
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-01-05T13:01:26Z
2021-01-05T13:01:26Z
2020-11-27
Microorganisms. 2020 Nov 27;8(12):1878. doi: 10.3390/microorganisms8121878.
2076-2607
33260910
10.3390/microorganisms8121878
http://hdl.handle.net/10033/622661
Microorganisms
Allergic airway inflammation (AAI) involves T helper cell type 2 (Th2) and pro-inflammatory responses to aeroallergens and many predisposing factors remain elusive. Influenza A virus (IAV) is a major human pathogen that causes acute respiratory infections and induces specific immune responses essential for viral clearance and resolution of the infection. Beyond acute infection, IAV has been shown to persistently affect lung homeostasis and respiratory immunity. Here we asked how resolved IAV infection affects subsequently induced AAI. Mice infected with a sublethal dose of IAV were sensitized and challenged in an ovalbumin mediated mouse model for AAI after resolution of the acute viral infection. Histological changes, respiratory leukocytes, cytokines and airway hyperreactivity were analyzed in resolved IAV infection alone and in AAI with and without previous IAV infection. More than five weeks after infection, we detected persistent pneumonia with increased activated CD4+ and CD8+ lymphocytes as well as dendritic cells and MHCII expressing macrophages in the lung. Resolved IAV infection significantly affected subsequently induced AAI on different levels including morphological changes, respiratory leukocytes and lymphocytes as well as the pro-inflammatory cytokine responses, which was clearly diminished. We conclude that IAV has exceptional persisting effects on respiratory immunity with substantial consequences for subsequently induced AAI.
en
MDPI
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
allergic airway inflammation
allergic asthma
influenza A virus
macrophages
pro-inflammatory cytokines
respiratory immune regulation
Resolved Influenza A Virus Infection Has Extended Effects on Lung Homeostasis and Attenuates Allergic Airway Inflammation in a Mouse Model.
Article
8
12
Microorganisms
Switzerland2021-01-05T13:01:27Zoai:repository.helmholtz-hzi.de:10033/6227992021-03-27T01:28:57Zcom_10033_311308com_10033_620591col_10033_620724col_10033_620721
Volckmar, Julia
Knop, Laura
Hirsch, Tatjana
Frentzel, Sarah
Erck, Christian
van Ham, Marco
Stegemann-Koniszewski, Sabine
Bruder, Dunja
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-03-26T12:21:46Z
2021-03-26T12:21:46Z
2021-02-05
J Vis Exp. 2021 Feb 5;(168). doi: 10.3791/62018.
33616089
10.3791/62018
http://hdl.handle.net/10033/622799
1940-087X
Journal of visualized experiments : JoVE
Targeted antigen delivery to cross-presenting dendritic cells (DC) in vivo efficiently induces T effector cell responses and displays a valuable approach in vaccine design. Antigen is delivered to DC via antibodies specific for endocytosis receptors such as DEC-205 that induce uptake, processing, and MHC class I- and II-presentation. Efficient and reliable conjugation of the desired antigen to a suitable antibody is a critical step in DC targeting and among other factors depends on the format of the antigen. Chemical conjugation of full-length protein to purified antibodies is one possible strategy. In the past, we have successfully established cross-linking of the model antigen ovalbumin (OVA) and a DEC-205-specific IgG2a antibody (αDEC-205) for in vivo DC targeting studies in mice. The first step of the protocol is the purification of the antibody from the supernatant of the NLDC (non-lymphoid dendritic cells)-145 hybridoma by affinity chromatography. The purified antibody is activated for chemical conjugation by sulfo-SMCC (sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate) while at the same time the sulfhydryl-groups of the OVA protein are exposed through incubation with TCEP-HCl (tris (2-carboxyethyl) phosphine hydrochloride). Excess TCEP-HCl and sulfo-SMCC are removed and the antigen is mixed with the activated antibody for overnight coupling. The resulting αDEC-205/OVA conjugate is concentrated and freed from unbound OVA. Successful conjugation of OVA to αDEC-205 is verified by western blot analysis and enzyme-linked immunosorbent assay (ELISA). We have successfully used chemically crosslinked αDEC-205/OVA to induce cytotoxic T cell responses in the liver and to compare different adjuvants for their potential in inducing humoral and cellular immunity following in vivo targeting of DEC-205+ DC. Beyond that, such chemically coupled antibody/antigen conjugates offer valuable tools for the efficient induction of vaccine responses to tumor antigens and have been proven to be superior to classical immunization approaches regarding the prevention and therapy of various types of tumors.
en
MyJove Corporation
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Chemical Conjugation of a Purified DEC-205-Directed Antibody with Full-Length Protein for Targeting Mouse Dendritic Cells In Vitro and In Vivo.
Article
168
Journal of visualized experiments : JoVE
United States
oai:repository.helmholtz-hzi.de:10033/6228152021-04-02T01:38:06Zcom_10033_620591col_10033_620725
Petry, Monique
Palus, Martin
Leitzen, Eva
Mitterreiter, Johanna Gracia
Huang, Bei
Kröger, Andrea
Verjans, Georges M G M
Baumgärtner, Wolfgang
Rimmelzwaan, Guus F
Růžek, Daniel
Osterhaus, Albert
Prajeeth, Chittappen Kandiyil
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-04-01T11:12:38Z
2021-04-01T11:12:38Z
2021-02-26
. Vaccines (Basel). 2021 Feb 26;9(3):196. doi: 10.3390/vaccines9030196.
2076-393X
33652698
10.3390/vaccines9030196
http://hdl.handle.net/10033/622815
Vaccines
Tick-borne encephalitis virus (TBEV) is a leading cause of vector-borne viral encephalitis with expanding endemic regions across Europe. In this study we tested in mice the efficacy of preinfection with a closely related low-virulent flavivirus, Langat virus (LGTV strain TP21), or a naturally avirulent TBEV strain (TBEV-280) in providing protection against lethal infection with the highly virulent TBEV strain (referred to as TBEV-Hypr). We show that prior infection with TP21 or TBEV-280 is efficient in protecting mice from lethal TBEV-Hypr challenge. Histopathological analysis of brains from nonimmunized mice revealed neuronal TBEV infection and necrosis. Neuroinflammation, gliosis, and neuronal necrosis was however also observed in some of the TP21 and TBEV-280 preinfected mice although at reduced frequency as compared to the nonimmunized TBEV-Hypr infected mice. qPCR detected the presence of viral RNA in the CNS of both TP21 and TBEV-280 immunized mice after TBEV-Hypr challenge, but significantly reduced compared to mock-immunized mice. Our results indicate that although TBEV-Hypr infection is effectively controlled in the periphery upon immunization with low-virulent LGTV or naturally avirulent TBEV 280, it may still enter the CNS of these animals. These findings contribute to our understanding of causes for vaccine failure in individuals vaccinated with TBE vaccines.
en
MDPI
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
CNS
Langat virus
neuronal damage
tick-borne encephalitis virus
virus induced immunity
Immunity to TBEV Related Flaviviruses with Reduced Pathogenicity Protects Mice from Disease but Not from TBEV Entry into the CNS.
Article
9
3
Vaccines
Switzerland2021-04-01T11:12:39Zoai:repository.helmholtz-hzi.de:10033/6228232021-04-08T01:40:59Zcom_10033_128109com_10033_620659com_10033_620591col_10033_128110col_10033_620724col_10033_620660
Elfaki, Yassin
Robert, Philippe A
Binz, Christoph
Falk, Christine S
Bruder, Dunja
Prinz, Immo
Floess, Stefan
Meyer-Hermann, Michael
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
2021-04-07T14:24:38Z
2021-04-07T14:24:38Z
2021-02-26
Eur J Immunol. 2021 Feb 26. doi: 10.1002/eji.202048981. Epub ahead of print.
33638148
10.1002/eji.202048981
http://hdl.handle.net/10033/622823
1521-4141
European journal of immunology
Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.
en
Wiley-VCH
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Foxp3+ Treg cells ⋅ Influenza A virus ⋅ Mathematical modeling ⋅ Ordinary differential equations ⋅ Thymus atrophy
Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.
Article
European journal of immunology
Germany2021-04-07T14:24:38Zoai:repository.helmholtz-hzi.de:10033/6228312021-04-20T02:45:37Zcom_10033_620591col_10033_620724
Roth, Stefan
Cao, Jiayu
Singh, Vikramjeet
Tiedt, Steffen
Hundeshagen, Gabriel
Li, Ting
Boehme, Julia D
Chauhan, Dhruv
Zhu, Jie
Ricci, Alessio
Gorka, Oliver
Asare, Yaw
Yang, Jun
Lopez, Mary S
Rehberg, Markus
Bruder, Dunja
Zhang, Shengxiang
Groß, Olaf
Dichgans, Martin
Hornung, Veit
Liesz, Arthur
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-04-19T12:18:57Z
2021-04-19T12:18:57Z
2021-03-04
Immunity. 2021 Apr 13;54(4):648-659.e8. doi: 10.1016/j.immuni.2021.02.004. Epub 2021 Mar 4.
33667383
10.1016/j.immuni.2021.02.004
http://hdl.handle.net/10033/622831
1097-4180
Immunity
Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1β (IL-1β) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia.
en
Elsevier (Cell Press)
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
AIM2
Fas
IL-1
T cell
burn
cell death
inflammasome
stroke
tissue injury
Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade.
Article
54
4
648
659.e8
Immunity
United States
oai:repository.helmholtz-hzi.de:10033/6229712021-08-07T03:28:45Zcom_10033_620591col_10033_620724
Hoang, Quynh Trang Mi
Nguyen, Van Kinh
Oberacher, Herbert
Fuchs, Dietmar
Hernandez-Vargas, Esteban A
Borucki, Katrin
Waldburg, Nadine
Wippermann, Jens
Schreiber, Jens
Bruder, Dunja
Veluswamy, Priya
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-07-29T14:31:42Z
2021-07-29T14:31:42Z
2021-06-08
Front Med (Lausanne). 2021 Jun 8;8:676058. doi: 10.3389/fmed.2021.676058.
2296-858X
34169084
10.3389/fmed.2021.676058
http://hdl.handle.net/10033/622971
Frontiers in medicine
COPD and asthma are two distinct but sometimes overlapping diseases exhibiting varying degrees and types of inflammation on different stages of the disease. Although several biomarkers are defined to estimate the inflammatory endotype and stages in these diseases, there is still a need for new markers and potential therapeutic targets. We investigated the levels of a phytohormone, abscisic acid (ABA) and its receptor, LANCL2, in COPD patients and asthmatics. In addition, PPAR-γ that is activated by ABA in a ligand-binding domain-independent manner was also included in the study. In this study, we correlated ABA with COPD-propagating factors to define the possible role of ABA, in terms of immune regulation, inflammation, and disease stages. We collected blood from 101 COPD patients, 52 asthmatics, and 57 controls. Bronchoscopy was performed on five COPD patients and 29 controls. We employed (i) liquid chromatography-tandem mass spectrometry and HPLC to determine the ABA and indoleamine 2,3-dioxygenase levels, respectively; (ii) real-time PCR to quantify the gene expression of LANCL2 and PPAR-γ; (iii) Flow cytometry to quantify adipocytokines; and (iv) immunoturbidimetry and ELISA to measure CRP and cytokines, respectively. Finally, a multinomial regression model was used to predict the probability of using ABA as a biomarker. Blood ABA levels were significantly reduced in COPD patients and asthmatics compared to age- and gender-matched normal controls. However, PPAR-γ was elevated in COPD patients. Intriguingly, ABA was positively correlated with immune-regulatory factors and was negatively correlated with inflammatory markers, in COPD. Of note, ABA was increased in advanced COPD stages. We thereby conclude that ABA might be involved in regulation of COPD pathogenesis and might be regarded as a potential biomarker for COPD stages.
en
Frontiers
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
COPD
LanCL2
PPAR-γ
abscisic acid
asthma
Serum Concentration of the Phytohormone Abscisic Acid Is Associated With Immune-Regulatory Mediators and Is a Potential Biomarker of Disease Severity in Chronic Obstructive Pulmonary Disease.
Article
8
676058
Frontiers in medicine
Switzerland2021-07-29T14:31:42Zoai:repository.helmholtz-hzi.de:10033/6230192021-09-09T01:53:31Zcom_10033_620591col_10033_620725
Kleinholz, Corinna L
Riek-Burchardt, Monika
Seiß, Elena A
Amore, Jonas
Gintschel, Patricia
Philipsen, Lars
Bousso, Philippe
Relja, Borna
Schraven, Burkhart
Handschuh, Juliane
Mohr, Juliane
Müller, Andreas J
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-09-08T13:27:15Z
2021-09-08T13:27:15Z
2021-07-23
Sci Rep. 2021 Jul 23;11(1):15071. doi: 10.1038/s41598-021-94425-9.
34302006
10.1038/s41598-021-94425-9
http://hdl.handle.net/10033/623019
2045-2322
Scientific reports
Neutrophils represent one of the first immune cell types recruited to sites of infection, where they can control pathogens by phagocytosis and cytotoxic mechanisms. Intracellular pathogens such as Leishmania major can hijack neutrophils to establish an efficient infection. However the dynamic interactions of neutrophils with the pathogen and other cells at the site of the infection are incompletely understood. Here, we have investigated the role of Ly6G, a homolog of the human CD177 protein, which has been shown to interact with cell adhesion molecules, and serves as a bona fide marker for neutrophils in mice. We show that Ly6G deficiency decreases the initial infection rate of neutrophils recruited to the site of infection. Although the uptake of L. major by subsequently recruited monocytes was tightly linked with the concomitant uptake of neutrophil material, this process was not altered by Ly6G deficiency of the neutrophils. Instead, we observed by intravital 2-photon microscopy that Ly6G-deficient neutrophils entered the site of infection with delayed initial recruitment kinetics. Thus, we conclude that by promoting neutrophils' ability to efficiently enter the site of infection, Ly6G contributes to the early engagement of intracellular pathogens by the immune system.
en
NPG
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Ly6G deficiency alters the dynamics of neutrophil recruitment and pathogen capture during Leishmania major skin infection.
Article
11
1
15071
Scientific reports
England2021-09-08T13:27:15Zoai:repository.helmholtz-hzi.de:10033/6231752022-05-06T01:50:39Zcom_10033_620591col_10033_620724
Aghapour, Mahyar
Remels, Alexander H V
Pouwels, Simon D
Bruder, Dunja
Hiemstra, Pieter S
Cloonan, Suzanne M
Heijink, Irene H
2022-05-05T13:04:06Z
2022-05-05T13:04:06Z
2019-11-06
2022-05-05
31693390
10.1152/ajplung.00329.2019
http://hdl.handle.net/10033/623175
1522-1504
American journal of physiology. Lung cellular and molecular physiology
Disturbances in mitochondrial structure and function in lung epithelial cells have been implicated in the pathogenesis of various lung diseases, including chronic obstructive pulmonary disease (COPD). Such disturbances affect not only cellular energy metabolism but also alter a range of indispensable cellular homeostatic functions in which mitochondria are known to be involved. These range from cellular differentiation, cell death pathways, and cellular remodeling to physical barrier function and innate immunity, all of which are known to be impacted by exposure to cigarette smoke and have been linked to COPD pathogenesis. Next to their well-established role as the first physical frontline against external insults, lung epithelial cells are immunologically active. Malfunctioning epithelial cells with defective mitochondria are unable to maintain homeostasis and respond adequately to further stress or injury, which may ultimately shape the phenotype of lung diseases. In this review, we provide a comprehensive overview of the impact of cigarette smoke on the development of mitochondrial dysfunction in the lung epithelium and highlight the consequences for cell function, innate immune responses, epithelial remodeling, and epithelial barrier function in COPD. We also discuss the applicability and potential therapeutic value of recently proposed strategies for the restoration of mitochondrial function in the treatment of COPD.
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
COPD
cigarette smoke
lung epithelial cells
mitochondrial dysfunction
Mitochondria: at the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease.
Article
318
1
L149
L164
American journal of physiology. Lung cellular and molecular physiology
United States2022-05-05T13:04:07Zoai:repository.helmholtz-hzi.de:10033/6232032022-06-14T01:56:10Zcom_10033_620591col_10033_620724
Boehme, Julia D
Frentzel, Sarah
Bruder, Dunja
2022-06-13T08:45:09Z
2022-06-13T08:45:09Z
2020-08-03
2020-07-09
32747686
10.1038/s41423-020-0517-5
http://hdl.handle.net/10033/623203
2042-0226
Cellular & molecular immunology
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
NMP4: a nuclear driver of innate inflammatory responses during influenza A virus infection.
Article
17
12
1220
1221
Cellular & molecular immunology
China2022-06-13T08:45:09Zoai:repository.helmholtz-hzi.de:10033/6232142022-06-14T01:56:25Zcom_10033_620591col_10033_620724
Sasaki, Karin
Bruder, Dunja
Hernandez-Vargas, Esteban A
2022-06-13T11:09:44Z
2022-06-13T11:09:44Z
2020-02-15
2019-10-07
1007-5704
32288422
10.1016/j.cnsns.2020.105228
http://hdl.handle.net/10033/623214
Communications in nonlinear science & numerical simulation
Co-infections by multiple pathogens have important implications in many aspects of
health, epidemiology and evolution. However, how to disentangle the non-linear dynamics
of the immune response when two infections take place at the same time is largely
unexplored. Using data sets of the immune response during influenza-pneumococcal coinfection
in mice, we employ here topological data analysis to simplify and visualise high
dimensional data sets.
We identified persistent shapes of the simplicial complexes of the data in the three infection
scenarios: single viral infection, single bacterial infection, and co-infection. The
immune response was found to be distinct for each of the infection scenarios and we
uncovered that the immune response during the co-infection has three phases and two
transition points. During the first phase, its dynamics is inherited from its response to
the primary (viral) infection. The immune response has an early shift (few hours post coinfection)
and then modulates its response to react against the secondary (bacterial) infection.
Between 18 and 26 h post co-infection the nature of the immune response changes
again and does no longer resembles either of the single infection scenarios.
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Complex data analysis
Immune system dynamics
Influenza infections
Topological data analysis
Topological data analysis to model the shape of immune responses during co-infections.
Article
85
105228
Communications in nonlinear science & numerical simulation
China2022-06-13T11:09:45Z