IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection.

Treg cells are crucial for immune homeostasis and for dampening immune response to several diseased conditions, including viral infections. Murine cytomegalovirus (MCMV) is a herpesvirus with pathogenic potential, so that early immune mechanisms are essential in controlling virus and protecting from virus-induced pathology. Studies on Foxp3+ Treg cells have revealed their inhibitory role on the early T cell response to MCMV infection and have suggested Treg cells as a target of MCMV’s immunoevasion mechanisms. Here we demonstrate that the number and activation status of liver Treg cells is strongly induced upon MCMV infection in order to protect the host from severe liver damage. They constitutively express high amounts of IL-33 receptor ST2 and their accumulation depends on IL-33, which is released as a tissue alarmin after the cell damage. For the first time, we show an immunoregulatory role of IL-33-dependent Treg cells in the liver of MCMV infected mice and their suppression of MCMV-induced immunopathology

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

The herpesvirus cytomegalovirus can cause severe morbidity in immunosuppressed people and poses a much greater global problem in the context of congenital infections than the Zika virus. To establish infection, cytomegalovirus needs to modulate the antiviral immune response of its host. One of the first lines of defense against viral infections is the type I interferon response which is activated by cellular sensors called pattern recognition receptors. These receptors sense viral entry and rapidly induce the transcription of type I interferons, which are instrumental for the induction of an antiviral state in infected and surrounding cells. We have identified the first viral protein encoded by murine cytomegalovirus, the M35 protein, that counteracts type I interferon transcription downstream of multiple pattern recognition receptors. We found that this viral countermeasure occurs shortly after viral entry into the host cell, as M35 is delivered with the viral particle. M35 then localizes to the nucleus where it modulates NF-κB-mediated transcription. In vivo, murine cytomegalovirus deficient of the M35 protein replicates to lower levels in spleen and liver and cannot establish a productive infection in the salivary glands, which is a key site of viral transmission, highlighting the important role of M35 for the establishment of infection. Our study provides novel insights into the complex interaction between cytomegalovirus and the innate immune response of its host

Ein Modellsystem zur Analyse der Cytomegalovirus-Pneumonie: Pathogenese, Praevention und Post-Exposure Therapie Schlussbericht

The infection with Human Herpesvirus Type 5 (HHV-5), the Human Cytomegalovirus (CMV), is a serious complication in immunocompromised patients, in particular in patients with AIDS and in solid organ or bone marrow transplantation recipients. Interstitial CMV pneumonia (CMV-IP) is the predominant manifestation of CMV disease and the most frequent viral cause of death, specifically after bone marrow transplantation (BMT). It was the aim of the investigation to employ a model system, namely murine CMV infection after experimental BMT, for studying the mechanisms of CMV pathogenesis in the lungs and for developing protocols for prophylaxis and therapy of CMV-IP. Infiltration of the lungs by protective CD8 T lymphocytes was identified as the key event in the control of a post-BMT CMV infection. Failure in the reconstitution of CD8 T lymphocytes in a Graft-versus-Host (GvH) genetics of the BMT or experimental in vivo depletion of the CD8 subset of T lymphocytes by anti-CD8 antibody resulted in lethal CMV disease characterized by focal spread of CMV within lung tissue. Molecular analysis of CMV latency by using polymerase chain reaction (PCR) for the detection of viral DNA in tissue identified the lungs as a high-risk organ for CMV latency and reccurence. Most importantly, the risk of recurrence correlated with the burden of latent CMV DNA in tissue. In conclusion, firstly, pan-T cell depletion, which includes the CD8 T lymphocytes, must be avoided in GvH prophylaxis regimens in cases of CMV infection. Secondly, substitution of bone marrow cells with immune antiviral CD8 T lymphocytes may be used for adoptive cytoimmunotherapy and prophylaxis of CMV-IP. Thirdly, the quantitation of latent CMV in tissue by PCR can serve as a predictor for the risk of CMV disease in transplantations. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(29,25) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Komplikation der Organtransplantation durch Herpesviren. Teilprojekt 1: Cytomegalovirus-Latenz in der Lunge und Entwicklung einer Vakzine mit rekombinanten inkompletten Viruspartikeln Schlussbericht

Available from TIB Hannover: DtF QN1(100,41) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung, Berlin (Germany)DEGerman

Komplikation der Organtransplantation durch Herpesviren. Teilprojekt: Die Lunge als Zielorgan der Cytomegalovirus Pathogenese und Latenz nach experimenteller MHC-differenter Knochenmarktransplantation Schlussbericht

Available from TIB Hannover: DtF QN1(58,11) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Porcine T-cell receptors: molecular and biochemical characterization.

Two subclasses of CD3 associated T-cell receptors (TcR) have been described so far, consisting of either an alpha and beta chain (TcR alpha beta) or a gamma and delta chain (TcR gamma delta). Of the two subclasses, the TcR alpha beta is the one predominantly expressed on peripheral T lymphocytes of humans and rodents. TcR gamma delta T lymphocytes represent only a minor subset in these species. Among all mammalian species studied so far, swine showed the most diversified composition of the T-lymphocyte population characterized by the expression of CD4 and CD8 differentiation antigens. Besides CD4+CD8- and CD4-CD8+ T lymphocytes, CD4+CD8+ and CD4-CD8- T lymphocytes are prominent in the extrathymic T-lymphocyte compartment. Because of the lack of specific monoclonal antibodies (mAb), to date the porcine TcR can only be characterized with biochemical and molecular biological methods. TcR on porcine peripheral blood T lymphocytes with the phenotype CD4+ and/or CD8+ are characterized as 46-48 kDaR heterodimers which were supposed to represent the porcine TcR alpha beta. Biochemical analyses of the CD4-CD8- T lymphocytes revealed three distinct TcR gamma delta; all are characterized by a 40 kDa delta chain but differed in their gamma chains. One gamma chain with a molecular mass of 38 kDaR is preferentially expressed on CD4-CD8- T lymphocytes derived from peripheral blood; another chain with molecular mass of 37 kDaR is evenly distributed between CD4-CD8- T lymphocytes from blood and lymphoid tissues.(ABSTRACT TRUNCATED AT 250 WORDS

The viral chemokine MCK-2 of murine cytomegalovirus promotes infection as part of a gH/gL/MCK-2 complex.

Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination