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

虽然1型干扰素(IFN-I)的抗病毒特性是不可否认的，但最近的研究报告称，在急性和持续性病毒感染中，干扰素-I信号的作用不断扩大，有些出人意料。在急性病毒感染后，干扰素-I信号通过诱导异常的炎症反应和炎性先天免疫细胞群的募集而增加发病率和死亡率。与病毒感染类似，干扰素-I信号被报道有助于保护和增加对细菌感染的易感性，并且在感染过程中产生的干扰素-I的量是细菌毒力的重要决定因素。此外，病毒感染后干扰素-I的产生增加与宿主对继发性细菌感染的易感性有关，其中一些继发性细菌感染可导致严重的发病率甚至死亡。尽管干扰素-I信号与细菌感染之间存在因果联系，但干扰素-I信号促进原发和继发细菌感染以及相关的发病率和死亡率的细胞和分子机制尚不完全清楚。泛素特异性多肽酶18(USP18)是一种ISG15异肽酶，是干扰素-I信号的负调控因子。USP18基因在病毒感染后或在干扰素-I刺激下迅速表达。USP18的缺失增强了干扰素-I的信号转导，并与JAK-STAT信号转导和转录激活因子(JAK-STAT)信号的延长有关。此外，USP18的缺失或反应性半胱氨酸(C61)的突变将ISG15从其靶蛋白上切割出来，延长了ISG15介导的ISG化，降低了病毒载量。尽管对USP18在病毒感染中的作用进行了大量研究，但USP18如何调控原发和继发细菌感染在很大程度上仍不清楚。我们最初假设USP18的缺失会促进原发和继发的单核细胞增多性李斯特菌(L.M.)给予干扰素-I信号的感染促进L.M感染/复制，而USP18缺失促进持续的干扰素-I信号。然而，在感染L.M.的USP18-/-小鼠后，我们意外地观察到细菌负荷减少，而不是增加。我们的初步结果表明，USP18作用于干扰素-I信号的下游，以支持原发细菌感染。此外，我们假设，干扰素-I介导的USP18表达的诱导是促进干扰素-I促进的细菌在初次病毒感染后合并感染的原因。

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.