Identification and Characterization of Interferon-Stimulated Regulators of Bacterial Infection




Perelman, Sofya

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The type I interferon activated transcriptional response is a critical antiviral defense mechanism, yet its role in bacterial pathogenesis remains less well characterized. Using an intracellular pathogen Listeria monocytogenes as a model bacterial pathogen, I sought to identify the roles of individual interferon-stimulated genes in context of bacterial infection. Previously, type I interferon has been implicated in both restricting and promoting L. monocytogenes growth and immune stimulatory functions in vivo. Here, I adapted a gain-of-function flow cytometry based approach to screen a library of more than 350 human type I interferon-stimulated genes for inhibitors and enhancers of Lm infection. I identify 6 genes, including UNC93B1, MYD88, AQP9, and TRIM14 that potently inhibit L. monocytogenes infection. These inhibitors act through both transcription-mediated (MYD88) and non-transcriptional mechanisms (TRIM14). Further, I identify and characterize the human high affinity immunoglobulin receptor FcγRIa as an enhancer of L. monocytogenes internalization. My data reveal that FcγRIa promotes L. monocytogenes uptake in the absence of known host L. monocytogenes internalization receptors (E-cadherin and c-Met) as well as bacterial surface internalins (InlA and InlB). Additionally, FcγRIa-mediated uptake occurs independently of L. monocytogenes opsonization or canonical FcγRIa signaling. Importantly, I established the contribution of FcγRIa to L. monocytogenes infection in phagocytic cells, thus potentially linking the interferon response to a novel bacterial uptake pathway. Finally, I demonstrate that L. monocytogenes virulence factor actin assembly-inducing protein (ActA) is required for the FcγRIa-mediated internalization, potentially acting as a bacterial ligand of FcγRIa. Together, these studies provide an experimental and conceptual basis for deciphering the role of type I interferon in bacterial defense and virulence at single-gene resolution.

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