The Interferon Stimulated Gene Product Lymphocyte Antigen 6 Complex, Locus E Promotes Entry of a Subset of Diverse RNA Viruses and Inhibits Infection by Coronaviruses

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Interferons (IFNs) contribute to cell-intrinsic antiviral immunity by inducing hundreds of IFN-stimulated genes (ISG). In a screen to identify novel antiviral factors, the Schoggins lab unexpectedly uncovered a subset of genes that enhanced viral infection. Here, I describe my personal efforts to study lymphocyte antigen 6, locus E (LY6E), a protein which was identified in the screen to enhance the infection of viruses from Flaviviridae, Orthomyxoviridae, Retroviridae, and Alphaviridae viral families. In my studies, I confirmed that LY6E promotes viral infection of viruses from the same families, as demonstrated by both ectopic overexpression and endogenous knockout approaches. Using influenza A virus (IAV) as a model, I narrowed the enhancing effect of LY6E specifically to the entry step of uncoating, which precedes release of the viral genome into the cytoplasm and is required for viral replication. I also observed that the viral enhancement phenotype is conserved across evolution, as orthologs from bat, rhesus macaque, and mouse exerted a similar effect. To understand the physiological relevance of viral enhancement at the cellular level, I generated Ly6e conditional knockout mice and crossed them to multiple Cre recombinase transgenic mouse strains. As a result, I obtained mice with specific ablation of Ly6e in distinct immune cell compartments. From both ex vivo and in vivo studies using the Ly6e knockout mice, I concluded that Ly6e in alveolar macrophages is important for optimal defense against IAV infection. Finally, in collaboration with the postdoctoral fellow Stephanie Pfaender, I have shown that LY6E also possesses potent antiviral activity against a distinct subset of enveloped RNA viruses. Cumulatively, my work has uncovered three unique ways by which the ISG LY6E may contribute to the antiviral immune response. This work also provides insight regarding the multi-faceted ways a single ISG can provide broad protection against infection by viruses from diverse viral families.

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