2024-03-29T10:07:55Zhttp://repository.helmholtz-hzi.de/oai/requestoai: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:10033/3462082019-08-30T11:37:23Zcom_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:10033/6011422019-08-30T11:26:12Zcom_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:10033/6206092019-08-30T11:35:13Zcom_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:10033/6211262019-08-30T11:32:17Zcom_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:10033/6228152021-04-02T01:38:06Zcom_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:10033/6230192021-09-09T01:53:31Zcom_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
England2021-09-08T13:27:15Z