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Abstract

Human norovirus (HNV) is a positive sense RNA virus that is the most common cause of gastroenteritis worldwide. Despite active interest in pursuing vaccination and therapies, there are currently no well-established cell culture or animal models for studying this virus or other well-characterized noroviruses. Murine norovirus (MNV) is a distinct yet closely related norovirus that replicates and can be grown in well-characterized cell culture systems and can cause measurable morbidity and mortality in mice, and is thus a useful proxy for HNV study. Recent work with MNV identified a proteinaceous receptor, murine CD300LF, as a major determinant of susceptibility to MNV. Depletion of CD300LF from an otherwise susceptible host cell results in resistance to the virus and expression of the virus on many common otherwise MNV-resistant immortalized cell lines results in susceptibility. Importantly, initial studies into CD300LF focused on the C57BL/6J-like variant of the protein found in a variety of inbred mouse lines, though other variants exist. Inoculation of bone marrow-derived macrophages (BMDMs) taken from I/LnJ mice yielded no detectable virus, suggesting resistance to the virus. After expression of the C57BL/6J variant of CD300LF on the otherwise-resistant I/LnJ BMDMs resulted in detectable viral replication, we hypothesized that endogenous I/LnJ CD300LF was nonfunctional as an MNV receptor. Expression of C57BL/6J and I/LnJ variants of CD300LF on the macrophage-like cell line BV2 yielded the same infection phenotypes for each variant. Comparison of these variants with a third variant, CAST/EiJ, led to the identification of a four amino acid cluster that differs between the original two variants that underlies their phenotype. Surprisingly, expression of either of these variants on other immortalized cell lines results in susceptibility to MNV, suggesting the existence of other determinants of CD300LF-mediated susceptibility to MNV. Influenza A virus (IAV) is a negative sense RNA virus that results in significant mortality worldwide each year from seasonal epidemics. Several known strains of IAV also pose the risk of becoming a pandemic threat via genomic reassortment in nonhuman hosts, often with significantly increased rates of mortality in exposed individuals. As attempts to create universal IAV vaccines have been unsuccessful, it becomes critical to understand the pathogenesis of pandemic strains to inform potential therapies to ensure widespread availability before such a pandemic. To this end, studies into H5N1, a strain of highly pathogenic avian influenza (HPAI) considered to be among the most dangerous have identified several key factors, including endothelial cell tropism as critical for pathogenesis. We attempted to expand the understanding of HPAI pathogenesis by probing the contribution of endothelial cell tropism to the virulence and pathogenesis of H7N7, another virulent HPAI strain with the capacity to infect humans. Introduction of sequences complementary to tissue-specific microRNA (miRNA) into H7N7 mRNA restricting replication in endothelial cells and monocyte derived cells do not indicate a major role for such tissue tropism, indicating distinct pathogenesis from H5N1. These investigations into the role of host factors for RNA viruses underscore the notion that viral replication cannot take place without contributions from a host and indicate the importance of understanding the interplay between host and pathogen.

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