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，但最近的研究报告了IFN-I信号传导在急性和持续性病毒感染期间的扩展和有点意想不到的作用。IFN-I信号传导可以通过诱导异常炎症反应和急性病毒感染后炎症性先天免疫细胞群的募集来促进发病率和死亡率。与病毒感染类似，已报道IFN-1信号传导有助于保护和增加对细菌感染的易感性，并且在感染期间产生的IFN-1的量是细菌毒力的重要决定因素。此外，病毒感染后IFN-I产生的升高与促进宿主对继发性细菌感染的易感性有因果关系，其中一些可能导致严重的发病率甚至死亡。尽管IFN-I信号传导和细菌感染之间存在因果关系，但IFN-I信号传导促进原发性和继发性细菌感染以及相关发病率和死亡率的细胞和分子机制尚不完全清楚。泛素特异性肽酶18（USP 18）被称为ISG 15异肽酶和IFN-I信号传导的负调节剂。USP 18基因在病毒感染后或通过IFN-I刺激迅速表达。USP 18的缺失增强了IFN-I的信号传导，并与延长的Janus激活激酶/信号转导和转录激活因子（JAK-STAT）信号传导相关。此外，缺乏USP 18或从其靶蛋白裂解ISG 15的反应性半胱氨酸（C61）突变，可使ISG 15介导ISG化并降低病毒载量。尽管对USP 18在病毒感染中的作用进行了大量研究，但USP 18如何调节原发性和继发性细菌感染仍在很大程度上未知。我们最初假设USP 18的缺失将促进初级和次级单核细胞增生李斯特菌（L.m.）给予IFN-1信号传导的感染促进L.m感染/复制，USP 18缺失促进持续的IFN-1信号传导。然而，在用L.m.感染USP 18-/-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，USP 18的行为下游的IFN-Ⅰ信号，以支持原发性细菌感染。此外，我们假设IFN-I介导的USP 18表达的诱导是促进IFN-I促进的细菌合并感染后的主要病毒感染的原因。

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.