Host immune response to mouse adenovirus type 1
Moore, Martin Lawrence
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Mouse adenovirus type 1 (MAV-1) provides a model of adenovirus pathogenesis. MAV-1 induces dose-dependent encephalomyelitis. To characterize the role of specific mechanisms of immunity in MAV-1-induced disease, immunodeficient mouse models were utilized. T cells, major histocompatibility complex class I, and perforin contributed to MAV-1- induced acute disease. Mice lacking á / T cells succumbed to MAV-1 infection 9 to 16 weeks post-infection. á / T cells were required for clearance of infectious MAV-1 and for long-term survival. Mice lacking CD8 + T cells and mice lacking CD4 + T cells cleared MAV-1 like controls. These data are consistent with a model in which CD8 + T cells induce acute immunopathology and either CD8 + T cells or CD4 + T cells are required for long-term control of MAV-1 replication. B cell-deficient mice were highly susceptible to acute MAV-1 infection and succumbed with high viral loads, disseminated infection, and hepatitis. It was hypothesized that a T cell-independent (TI) B cell response is the critical protective mechanism. Bruton’s tyrosine kinase-deficient mice have reduced numbers of B cells and are unable to mount TI B cell responses to some antigens. Loss of Btk in mice results in the classic X-linked immunodeficiency (Xid) phenotype. Btk was required for survival of acute MAV-1 infection, demonstrating for the first time that Btk plays a role in protection from virus-induced disease in mice. Survival of acute MAV-1 infection correlated with TI antiviral IgM production, and treatment of lethally infected Btk-deficient mice with early anti-MAV-1 antiserum was protective. The role of interferon-á / (IFN-á /) signaling in MAV-1 infection was investigated using IFN-á / receptor null mice (IFN-á /R -/- ). Surprisingly, MAV-1 virulence and replication in the brain was not significantly altered in IFN-á /R -/- mice relative to control mice. However, IFN-á /R -/- mice exhibited a more disseminated MAV-1 infection than controls, indicating that IFN-á / is a determinant of MAV-1 organ tropism. IFN-stimulated genes (ISGs) whose steady-state mRNA levels were increased by MAV-1 infection in vitro and in vivo were identified. Northern analyses of mRNAs in infected mice suggest that interferon regulatory factor 7 and major histocompatibility complex class I play a role in IFN-á / signaling-dependent control of MAV-1 organ tropism.