The probacterial effect of type I interferon signaling requires its own negative regulator USP18

Abstract

Type I interferon (IFN-I) signaling paradoxically impairs host immune responses during many primary and secondary bacterial infections. Lack of IFN-I receptor reduces bacterial replication and/or bacterial persistence during infection with several bacteria. However, the mechanisms that mediate the adverse IFN-I effect are incompletely understood. Here, we show that Usp18, an interferon-stimulated gene that negatively regulates IFN-I signaling, is primarily responsible for the deleterious effect of IFN-I signaling during infection of mice with Listeria monocytogenes or Staphylococcus aureus. Mechanistically, USP18 promoted bacterial replication by inhibiting antibacterial tumor necrosis factor-α (TNF-α) signaling. Deleting IFNAR1 or USP18 in CD11c-Cre+ cells similarly reduced bacterial titers in multiple organs and enhanced survival. Our results demonstrate that inhibiting USP18 function can promote control of primary and secondary bacterial infection by enhancing the antibacterial effect of TNF-α, which correlates with induction of reactive oxygen species (ROS). These findings suggest that USP18 could be targeted therapeutically in patients to ameliorate disease caused by serious bacterial infections.

Versatility of USP18 in physiology and pathophysiology

“…It is possible that USP18 may also involve other USPs and suppress TNF-α in different pathways. Such a relationship was described for USP20 which deubiquitinates mitochondrial adaptor protein STING (stimulator of interferon genes) Shaabani et al, 2018). However, other authors have shown that this recruitment, leading to STING stabilization, sustains cellular antiviral responses and decreases susceptibility to HSV-1 .…”

“…IFNAR1 or Usp18 knock-out CD11c-Cre+ cells were observed to mitigate bacterial titres in several organs and to prolong survival. This phenomenon was proven to be independent of the IFNAR2 binding and isopeptidase domains (Shaabani et al, 2018). It is possible that USP18 may also involve other USPs and suppress TNF-α in different pathways.…”

“…Ubiquitin-specific peptidase 18 (USP18) is a cysteine protease of a dual nature. As an enzyme, it cleaves ubiquitin-like molecules (Ubls) from their target proteins, while as a substrate for an interferon (IFN) receptor it acts as an IFN type I and III signalling suppressor (Hoeller et al, 2006;Manini at al., 2013;Hong et al, 2014;Ketscher & Knobeloch, 2015;Honke et al, 2016;Mac-Parland et al, 2016;An et al, 2017;Basters et al, 2017;Mustachio et al, 2017;Basters et al, 2018;Shaabani et al, 2018;Gu et al, 2019). These diverse functions make USP18 an interesting object for research and many studies describing this unique molecule have been published recently.…”

“…These diverse functions make USP18 an interesting object for research and many studies describing this unique molecule have been published recently. Among others, its contribution to cell signalling, response to viral and bacterial infections, development of several malignancies and development of autoimmune diseases have been described (Liu et al, 1999;Ritchie et al, 2004;Hoeller et al, 2006;Catic et al, 2007;Duex & Sorkin, 2009;François-Newton et al, 2011;Murray et al, 2011;Burkart et al, 2012;Guo et al, 2012;Yim et al, 2012;Coit et al, 2013;Honke et al, 2013;Hong et al, 2014;Zhang et al, 2015;Honke et al, 2016;Ying et al, 2016;An et al, 2017;Arimoto et al, 2017;Basters et al, 2017;Mustachio et al, 2017;Basters et al, 2018;Shaabani et al, 2018;Gu et al, 2019). USP18 was also found to serve as an inhibitor of cardiac remodelling (Ying et al, 2016).…”

ISG15 drives immune pathology and respiratory failure during viral infection

“…Type I interferon (IFN-I) is one of the first cytokines induced during viral infection and plays an essential role in orchestrating effective immune responses due to its induction of antiviral genes and as an immune stimulant promoting cytokine/chemokine production, upregulating activation receptors, recruiting immune cells to infected tissues and facilitating optimal antigen presentation to T cells (McNab et al, 2015). Despite the central role of IFN-I in promoting an antiviral state, deleterious consequences of IFN-I signaling during viral infection have been reported (Ng et al, 2015; Shaabani et al, 2018; Teijaro et al, 2013; Wilson et al, 2013). An elevated IFN-I gene signature correlates with disease severity following influenza virus, lymphocytic choriomeningitis virus and severe acute respiratory syndrome (SARS)-Coronavirus (SARS-CoV) infections (Baccala et al, 2014; Channappanavar et al, 2016; Davidson et al, 2014; Davidson et al, 2015; Teijaro, 2016; Teijaro et al, 2011).…”