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Loss of Fas (CD95) expression by dendritic cells protects from a chronic viral infection

ABSTRACT: Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses.

ORGANISM(S): Mus musculus

PROVIDER: GSE57443 | GEO | 2014/05/09

SECONDARY ACCESSION(S): PRJNA246466

REPOSITORIES: GEO

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Project description:Rhesus macaques (Macaca mulatta) infected with a lethal dose of lymphocytic choriomeningitis virus-strain WE (LCMV-WE) provide a model for Lassa fever virus infection of man. Like Lassa fever in human beings, disease begins with flu-like symptoms but can progress to morbidity fairly rapidly. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al. J. Virol. 2007: PMID 17522210) showing distinct pre-viremic and viremic stages that discriminated between virulent and benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased. We observed gene expression changes that occurred before the viremic stage of the disease, and could potentially serve as biomarkers that discriminate between exposure to a hemorrhagic fever virus and exposure to a benign virus. Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a much broader effect on liver cell function than non-virulent virus. During the first few days of infection, virulent virus impacted gene expression associated with the generation of energy, such as fatty acid metabolism and glucose metabolism, with the complement and coagulation cascades, and with steroid metabolism, MAPK signaling and cell adhesion. For example, the energy profile resembled that of an organism entering starvation: acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis, was shut down and gene products involved in gluconeogenesis were up-regulated. In conclusion, this study identifies several potential gene markers of LCMV-WE-associated liver disease and contributes to the database of gene expression changes correlated with LCMV pathogenesis in primates. 6 groups: uninfected controls, LCMV-WE infected (pre-viremic; day 1 to day 3), LCMV-WE infected (viremic; day 4 to day 7), LCMV-WE infected (post-viremic; day 8 to day 12), LCMV-Armstrong (LCMV-ARM; non-virulent strain) infected, and LCMV-ARM/LCMV-WE infected but not diseased. Each sample is from the liver of a different rhesus macaque.

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Loss of Fas (CD95) expression by dendritic cells protects from a chronic viral infection

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