The functional role of the type 1 interferon-inducible Ubiquitin Specific Peptidase 18 (USP18) during primary and secondary bacterial infection.

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While the antiviral properties of type 1 interferon (IFN-I) are undeniable, recent studies have reported expanding and somewhat unexpected roles of IFN-I signaling during both acute and persistent viral infections. IFN-I signaling can promote morbidity and mortality through induction of aberrant inflammatory responses and recruitment of inflammatory innate immune cell populations following acute viral infection. Similar to viral infection, IFN-I signaling has been reported to both contribute to protection and increase susceptibility to bacterial infections and the amount of IFN-I produced during infection is an important determinant of bacterial virulence. Moreover, elevated IFN-I production following viral infection has been causally linked with promoting host susceptibility to secondary bacterial infections, some which can result in severe morbidity and even death. Despite a causal link between IFN-I signaling and bacterial infection, the cellular and molecular mechanisms by which IFN-I signaling promotes primary and secondary bacterial infection and associated morbidity and mortality are incompletely understood. Ubiquitin-specific peptidase 18 (USP18) is known as an ISG15 isopeptidase and a negative regulator of IFN-I signaling. The USP18 gene is rapidly expressed after viral infection or by stimulation with IFN-I. The absence of USP18 strengthens the signaling of IFN-I and is associated with prolonged Janus-activated kinase/signal transducer and activator of transcription (JAK-STAT) signaling. In addition, absence of USP18 or mutation of the reactive cysteine (C61), which cleaves ISG15 from its target protein, prolongs ISG15 mediated ISGylation and reduces viral load. Despite numerous studies on the role of USP18 in viral infection, how USP18 regulates both primary and secondary bacterial infection is still largely unknown. We initially hypothesized that deletion of USP18 would promote both primary and secondary Listeria monocytogenes (L.m.) infection given IFN-I signaling promotes L.m infection/replication and USP18 deletion promotes sustained IFN-I signaling. However, upon infection of USP18-/- mice with L.m., we unexpectedly observed reduced, rather than increased, bacterial load. Our preliminary results suggest that USP18 acts downstream of IFN-I signaling to support primary bacterial infection. Furthermore, we hypothesize that IFN-I mediated induction of USP18 expression is causal in promoting IFN-I-facilitated bacterial co-infection following primary viral infection.