Cell intrinsic antiviral mechanisms targeting human enteroviruses

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Project Summary Enteroviruses A, B, C, D are important pathogens that can cause a range of diseases including myocarditis, encephalitis, meningitis, conjunctivitis, hand, foot and mouth disease, and acute flaccid myelitis. Disease outcomes can be severe or fatal, particularly in neonates and children. The host innate immune response generally controls these viruses. However, the cell intrinsic antiviral mechanisms that mediate this host defense are not well defined. Here, we propose to identify and characterize host antiviral genes encoding both constitutively expressed (non-inducible) and interferon-stimulated gene (ISG) antiviral effectors. In Aim1, we will examine TRIM7, a constitutively expressed E3 ligase that we recently showed inhibits enterovirus replication by targeting a viral protein for degradation. We hypothesize that TRIM7 is a pan- enterovirus restriction factor in vitro and in vivo. In Aim 2, we will leverage our expertise in ISG screening technology to test the hypothesis that only a limited set of genes are true effectors of the interferon-induced antiviral response to enteroviruses A-D. We will characterize antiviral effector mechanisms of action, and we will use novel lipid nanoparticle gene delivery strategies to demonstrate antiviral efficacy in vivo. Both Aims will be achieved by a combination of biochemical, virological, and genetic approaches in cell-based assays and in mouse models of enterovirus infection and pathogenesis. Completion of the proposed aims will provide fundamental knowledge about the specific molecules that confer cell intrinsic protection against these enteroviruses. These studies may additionally inform the development of pan-enterovirus therapies based on the mechanisms of these naturally occurring antiviral defense proteins.