Recent Submissions

  • Humanized mouse model supports development, function, and tissue residency of human natural killer cells.

    Herndler-Brandstetter, Dietmar; Shan, Liang; Yao, Yi; Stecher, Carmen; Plajer, Valerie; Lietzenmayer, Melanie; Strowig, Till; de Zoete, Marcel R; Palm, Noah W; Chen, Jie; Blish, Catherine A; Frleta, Davor; Gurer, Cagan; Macdonald, Lynn E; Murphy, Andrew J; Yancopoulos, George D; Montgomery, Ruth R; Flavell, Richard A; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-11-07)
    Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2-/- Il2rg-/- background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg-/- (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt's lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.
  • The gut microbiota drives the impact of bile acids and fat source in diet on mouse metabolism.

    Just, Sarah; Mondot, Stanislas; Ecker, Josef; Wegner, Katrin; Rath, Eva; Gau, Laura; Streidl, Theresa; Hery-Arnaud, Genevieve; Schmidt, Sinah; Lesker, Till Robin; Bieth, Valentin; Dunkel, Andreas; Strowig, Till; Hofmann, Thomas; Haller, Dirk; Liebisch, Gerhard; Gérard, Philippe; Rohn, Sascha; Lepage, Patricia; Clavel, Thomas; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-08-02)
    As the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice. In combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism. Caution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum.
  • Humanized mouse model supports development, function, and tissue residency of human natural killer cells.

    Herndler-Brandstetter, Dietmar; Shan, Liang; Yao, Yi; Stecher, Carmen; Plajer, Valerie; Lietzenmayer, Melanie; Strowig, Till; de Zoete, Marcel R; Palm, Noah W; Chen, Jie; Blish, Catherine A; Frleta, Davor; Gurer, Cagan; Macdonald, Lynn E; Murphy, Andrew J; Yancopoulos, George D; Montgomery, Ruth R; Flavell, Richard A; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-11-07)
    Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (
  • Chronic d-serine supplementation impairs insulin secretion.

    Suwandhi, Lisa; Hausmann, Simone; Braun, Alexander; Gruber, Tim; Heinzmann, Silke S; Gálvez, Eric J C; Buck, Achim; Legutko, Beata; Israel, Andreas; Feuchtinger, Annette; Haythorne, Elizabeth; Staiger, Harald; Heni, Martin; Häring, Hans-Ulrich; Schmitt-Kopplin, Philippe; Walch, Axel; Cáceres, Cristina García; Tschöp, Matthias H; Rutter, Guy A; Strowig, Till; Elsner, Martin; Ussar, Siegfried; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-07-25)
    The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
  • Identification of a Predominantly Interferon-λ-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells.

    Selvakumar, Tharini A; Bhushal, Sudeep; Kalinke, Ulrich; Wirth, Dagmar; Hauser, Hansjörg; Köster, Mario; Hornef, Mathias W; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-01-01)
    Type I (α and β) and type III (λ) interferons (IFNs) induce the expression of a large set of antiviral effector molecules
  • Large-scale production of megakaryocytes in microcarrier-supported stirred suspension bioreactors.

    Eicke, Dorothee; Baigger, Anja; Schulze, Kai; Latham, Sharissa L; Halloin, Caroline; Zweigerdt, Robert; Guzman, Carlos A; Blasczyk, Rainer; Figueiredo, Constança; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-07-05)
    Megakaryocytes (MKs) are the precursors of platelets (PLTs) and may be used for PLT production in vivo or in vitro, as well as a source for PLT-derived growth factors. Induced pluripotent stem cells represent an unlimited cell source for the in vitro production of MKs. This study aimed at developing an effective, xeno-free and scalable system to produce high numbers of MKs. In particular, microcarrier beads-assisted stirred bioreactors were evaluated as a means of improving MK yields. This method resulted in the production of 18.7 × 10
  • Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis.

    Borst, Katharina; Frenz, Theresa; Spanier, Julia; Tegtmeyer, Pia-Katharina; Chhatbar, Chintan; Skerra, Jennifer; Ghita, Luca; Namineni, Sukumar; Lienenklaus, Stefan; Köster, Mario; Heikenwaelder, Mathias; Sutter, Gerd; Kalinke, Ulrich; TWINCORE, Zentrum für experimentelle und klinischeInfektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany. (2017-12-21)
    Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-β induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1 VACV infection induced local IFN-β responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis.
  • Induction of CD4(+) and CD8(+) anti-tumor effector T cell responses by bacteria mediated tumor therapy.

    Stern, Christian; Kasnitz, Nadine; Kocijancic, Dino; Trittel, Stephanie; Riese, Peggy; Guzman, Carlos A; Leschner, Sara; Weiss, Siegfried; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2015-10-15)
    Facultative anaerobic bacteria like E. coli can colonize solid tumors often resulting in tumor growth retardation or even clearance. Little mechanistic knowledge is available for this phenomenon which is however crucial for optimization and further implementation in the clinic. Here, we show that intravenous injections with E. coli TOP10 can induce clearance of CT26 tumors in BALB/c mice. Importantly, re-challenging mice which had cleared tumors showed that clearance was due to a specific immune reaction. Accordingly, lymphopenic mice never showed tumor clearance after infection. Depletion experiments revealed that during induction phase, CD8(+) T cells are the sole effectors responsible for tumor clearance while in the memory phase CD8(+) and CD4(+) T cells were involved. This was confirmed by adoptive transfer. CD4(+) and CD8(+) T cells could reject newly set tumors while CD8(+) T cells could even reject established tumors. Detailed analysis of adoptively transferred CD4(+) T cells during tumor challenge revealed expression of granzyme B, FasL, TNF-α and IFN-γ in such T cells that might be involved in the anti-tumor activity. Our findings should pave the way for further optimization steps of this promising therapy.
  • Self-Amplifying Replicon RNA Delivery to Dendritic Cells by Cationic Lipids

    Englezou, Pavlos C.; Sapet, Cedric; Démoulins, Thomas; Milona, Panagiota; Ebensen, Thomas; Schulze, Kai; Guzman, Carlos-Alberto; Poulhes, Florent; Zelphati, Olivier; Ruggli, Nicolas; McCullough, Kenneth C.; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
  • Memory CD8 T cells support the maintenance of hematopoietic stem cells in the bone marrow

    Geerman, Sulima; Brasser, Giso; Bhushal, Sudeep; Salerno, Fiamma; Kragten, Natasja A.; Hoogenboezem, Mark; de Haan, Gerald; Wolkers, Monika C.; Pascutti, María Fernanda; Nolte, Martijn A.; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
  • The chromatin remodeling factor SPOC1 acts as a cellular restriction factor against human cytomegalovirus by repressing the major immediate-early promoter.

    Reichel, Anna; Stilp, Anne-Charlotte; Scherer, Myriam; Reuter, Nina; Lukassen, Sören; Kasmapour, Bahram; Schreiner, Sabrina; Cicin-Sain, Luka; Winterpacht, Andreas; Stamminger, Thomas; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-09)
    The cellular protein SPOC1 (survival time-associated PHD finger protein in ovarian cancer 1) acts as a regulator of chromatin structure and DNA damage response. It binds H3K4me2/3 containing chromatin and promotes DNA condensation by recruiting corepressors such as KAP-1 and H3K9 methyltransferases. Previous studies identified SPOC1 as a restriction factor against human adenovirus (HAdV) infection that is antagonized by E1B-55K/E4orf6-dependent proteasomal degradation. Here, we demonstrate that, in contrast to HAdV-infected cells, SPOC1 is transiently upregulated during the early phase of HCMV replication. We show that expression of the immediate-early protein 1 (IE1) is sufficient and necessary to induce SPOC1. Additionally, we discovered that during later stages of infection SPOC1 is downregulated in a GSK-3β-dependent manner. We provide evidence that SPOC1 overexpression severely impairs HCMV replication by repressing the initiation of viral immediate early (IE) gene expression. Consistently, we observed that SPOC1-depleted primary human fibroblasts displayed augmented initiation of viral IE gene expression. This occurs in a MOI-dependent manner, a defining hallmark of intrinsic immunity. Interestingly, repression requires the presence of high SPOC1 levels at the start of infection while a later upregulation had no negative impact suggesting distinct temporal roles of SPOC1 during the HCMV replicative cycle. Mechanistically, we observed a highly specific association of SPOC1 with the major immediate-early promoter (MIEP) strongly suggesting that SPOC1 inhibits HCMV replication by MIEP binding and subsequent recruitment of heterochromatin building factors. Thus, our data add SPOC1 as a novel factor to the endowment of a host cell to restrict cytomegalovirus infections.
  • The chromatin remodeling factor SPOC1 acts as a cellular restriction factor against human cytomegalovirus by repressing the major immediate-early promoter.

    Reichel, Anna; Stilp, Anne-Charlotte; Scherer, Myriam; Reuter, Nina; Lukassen, Sören; Kasmapour, Bahram; Schreiner, Sabrina; Cicin-Sain, Luka; Winterpacht, Andreas; Stamminger, Thomas; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-09)
    The cellular protein SPOC1 (survival time-associated PHD finger protein in ovarian cancer 1) acts as a regulator of chromatin structure and DNA damage response. It binds H3K4me2/3 containing chromatin and promotes DNA condensation by recruiting corepressors such as KAP-1 and H3K9 methyltransferases. Previous studies identified SPOC1 as a restriction factor against human adenovirus (HAdV) infection that is antagonized by E1B-55K/E4orf6-dependent proteasomal degradation. Here, we demonstrate that, in contrast to HAdV-infected cells, SPOC1 is transiently upregulated during the early phase of HCMV replication. We show that expression of the immediate-early protein 1 (IE1) is sufficient and necessary to induce SPOC1. Additionally, we discovered that during later stages of infection SPOC1 is downregulated in a GSK-3β-dependent manner. We provide evidence that SPOC1 overexpression severely impairs HCMV replication by repressing the initiation of viral immediate early (IE) gene expression. Consistently, we observed that SPOC1-depleted primary human fibroblasts displayed augmented initiation of viral IE gene expression. This occurs in a MOI-dependent manner, a defining hallmark of intrinsic immunity. Interestingly, repression requires the presence of high SPOC1 levels at the start of infection while a later upregulation had no negative impact suggesting distinct temporal roles of SPOC1 during the HCMV replicative cycle. Mechanistically, we observed a highly specific association of SPOC1 with the major immediate-early promoter (MIEP) strongly suggesting that SPOC1 inhibits HCMV replication by MIEP binding and subsequent recruitment of heterochromatin building factors. Thus, our data add SPOC1 as a novel factor to the endowment of a host cell to restrict cytomegalovirus infections. Accumulating evidence indicates that during millennia of co-evolution host cells have developed a sophisticated compilation of cellular factors to restrict cytomegalovirus infections. Defining this equipment is important to understand cellular barriers against viral infection and to develop strategies to utilize these factors for antiviral approaches. So far, constituents of PML nuclear bodies and the interferon gamma inducible protein 16 (IFI16) were known to mediate intrinsic immunity against HCMV. In this study, we identify the chromatin modulator SPOC1 as a novel restriction factor against HCMV. We show that pre-existing high SPOC1 protein levels mediate a silencing of HCMV gene expression via a specific association with an important viral -regulatory element, the major immediate-early promoter. Since SPOC1 expression varies between cell-types, this factor may play an important role in the tissue-specific defense against HCMV.
  • Successful Fecal Microbiota Transplantation in a Patient with Severe Complicated Clostridium difficile Infection after Liver Transplantation.

    Schneider, Kai Markus; Wirtz, Theresa H; Kroy, Daniela; Albers, Stefanie; Neumann, Ulf Peter; Strowig, Till; Sellge, Gernot; Trautwein, Christian; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-18)
    Clostridium difficile infection (CDI) represents one of the most common healthcare-associated infections. Due to increasing numbers of recurrences and therapy failures, CDI has become a major disease burden. Studies have shown that fecal microbiota transplantation (FMT) can both be a safe and highly efficacious therapy for patients with therapy-refractory CDI. However, patients undergoing solid organ transplantation are at high risk for CDI due to long-term immunosuppression, previous antibiotic therapy, and proton pump inhibitor use. Additionally, these patients may be especially prone to adverse events related to FMT. Here, we report a successful FMT in a patient with severe therapy-refractory CDI after liver transplantation.
  • Tissue maintenance of CMV-specific inflationary memory T cells by IL-15.

    Baumann, Nicolas S; Torti, Nicole; Welten, Suzanne P M; Barnstorf, Isabel; Borsa, Mariana; Pallmer, Katharina; Oduro, Jennifer D; Cicin-Sain, Luka; Ikuta, Koichi; Ludewig, Burkhard; Oxenius, Annette; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-04)
    Cytomegalovirus (CMV) infection induces an atypical CD8 T cell response, termed inflationary, that is characterised by accumulation and maintenance of high numbers of effector memory like cells in circulation and peripheral tissues-a feature being successfully harnessed for vaccine purposes. Although stability of this population depends on recurrent antigen encounter, the requirements for prolonged survival in peripheral tissues remain unknown. Here, we reveal that murine CMV-specific inflationary CD8 T cells are maintained in an antigen-independent manner and have a half-life of 12 weeks in the lung tissue. This half-life is drastically longer than the one of phenotypically comparable inflationary effector cells. IL-15 alone, and none of other common γ-cytokines, was crucial for survival of inflationary cells in peripheral organs. IL-15, mainly produced by non-hematopoietic cells in lung tissue and being trans-presented, promoted inflationary T cell survival by increasing expression of Bcl-2. These results indicate that inflationary CD8 T cells are not just simply effector-like cells, rather they share properties of both effector and memory CD8 T cells and they appear to be long-lived cells compared to the effector cells from acute virus infections.
  • Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection.

    Sanchez Alberti, Andrés; Bivona, Augusto E; Cerny, Natacha; Schulze, Kai; Weißmann, Sebastian; Ebensen, Thomas; Morales, Celina; Padilla, Angel M; Cazorla, Silvia I; Tarleton, Rick L; Guzmán, Carlos A; Malchiodi, Emilio L; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017)
    The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections.
  • The Contribution of Cytomegalovirus Infection to Immune Senescence Is Set by the Infectious Dose.

    Redeker, Anke; Remmerswaal, Ester B M; van der Gracht, Esmé T I; Welten, Suzanne P M; Höllt, Thomas; Koning, Frits; Cicin-Sain, Luka; Nikolich-Žugich, Janko; Ten Berge, Ineke J M; van Lier, René A W; van Unen, Vincent; Arens, Ramon; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017)
    The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence. We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8+ T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8+ T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose. Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8+ T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.
  • Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor.

    Stichling, Nicole; Suomalainen, Maarit; Flatt, Justin W; Schmid, Markus; Pacesa, Martin; Hemmi, Silvio; Jungraithmayr, Wolfgang; Maler, Mareike D; Freudenberg, Marina A; Plückthun, Andreas; May, Tobias; Köster, Mario; Fejer, György; Greber, Urs F; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-03)
    Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage-like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses.
  • Virulence traits of environmental and clinicalLegionella pneumophilaMLVA genotypes.

    Sharaby, Yehonatan; Rodríguez-Martínez, Sarah; Pecellin, Marina; Sela, Rotem; Peretz, Avi; Höfle, Manfred; Halpern, Malka; Brettar, Ingrid; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-03-09)
    Legionella pneumophila causes water-based infections resulting in severe pneumonia. Recently, we showed that different variable numbers of tandem repeat analysis (MLVA-8) genotypes dominated different sites of a drinking-water distribution system, with a genotype-related temperature and abundance regime. Here we compare the pathogenicity potential of different MLVA-8 genotypes of environmental and clinical strains. The virulence traits studied were hemolytic activity and cytotoxicity towards amoebae and macrophages. Clinical strains were significantly more hemolytic than environmental strains, while their cytotoxicity towards amoebae was significantly lower at 30°C. No significant differences were detected between clinical and environmental strains in cytotoxicity towards macrophages. Significant differences in virulence were observed between the environmental genotypes (Gt). Gt15 strain showed a significantly higher hemolytic activity. In contrast, Gt4 and Gt6 strains were more infective towardsAcanthamoeba castellaniiMoreover, Gt4 strain exhibited increased cytotoxicity towards macrophages and demonstrated a broader temperature range of amoebal lysis compared to Gt6 and Gt15. Understanding the virulence traits ofLegionellagenotypes may improve the assessment of public health risks ofLegionellain drinking water.ImportanceLegionella pneumophilais the causative agent of a severe form of pneumonia. Here we demonstrate that clinical strains were significantly more cytotoxic towards red blood cells compared to environmental strains, while their cytotoxicity towards macrophages was similar. Genotype 4 (Gt4) strains were highly cytotoxic towards amoebae, macrophages, and lysed amoebae in a broader temperature range, compared to the other studied genotypes. The results can explain the Gt4 relatively high success in the environment and in clinical samples; thus Gt4 strains should be considered as a main factor for the assessment of public health risks ofLegionellain drinking water. Our findings shed light on the ecology, virulence, and pathogenicity potential of differentL. pneumophilagenotypes that can be a valuable parameter for future modelling and Quantitative Microbial Risk Assessment ofLegionellain drinking water systems.
  • Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency.

    Heine, Wiebke; Beckstette, Michael; Heroven, Ann Kathrin; Thiemann, Sophie; Heise, Ulrike; Nuss, Aaron Mischa; Pisano, Fabio; Strowig, Till; Dersch, Petra; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02)
    Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style.
  • The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.

    Hu, Bo; Jin, Chengcheng; Li, Hua-Bing; Tong, Jiyu; Ouyang, Xinshou; Cetinbas, Naniye Malli; Zhu, Shu; Strowig, Till; Lam, Fred C; Zhao, Chen; Henao-Mejia, Jorge; Yilmaz, Omer; Fitzgerald, Katherine A; Eisenbarth, Stephanie C; Elinav, Eran; Flavell, Richard A; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
    Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.

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