UNC93B1 Mediates Innate Inflammation and Antiviral Defense in the Liver during Acute Murine Cytomegalovirus Infection

Crane, Meredith J.; Gaddi, Pamela J.; Salazar-Mather, Thais P.

The aim of these studies was to identify the TLR signaling pathways required for the innate recognition of virus infection in the liver, a common target organ of many viruses that significantly contributes to innate immune defenses [38] [39] [40] . Moreover, the liver contains various innate immune cells that express TLRs [41, 42] ; however, the role of TLRs in host defense against infection at this site remains largely unclear. Because responses in the liver do not appear dependent on individual TLRs [6, 20, 32] , we utilized 3d mice, which lack endosomal TLR3, TLR7 and TLR9 signaling due to a mutation in the endoplasmic reticulumresident protein UNC93B1 [34, 35] , to address the contribution of endosomal TLRs in liver antiviral defenses against acute MCMV infection. The results demonstrated impaired production of proinflammatory cytokines by NK cells and pDCs in livers from MCMV-infected 3d mice. Additionally, 3d mice had elevated viral titers in the liver that coincided with transient but exacerbated liver disease, although virus-specific CD8+ T cell responses were not affected. Interestingly, a previous study demonstrated that TLR3 was not required for the generation of adaptive antiviral responses to MCMV [43] , although there is evidence that TLR3 signaling contributes in part to the early control of MCMV infection by the systemic induction of type I IFN [6] . Other studies have implicated a synergistic role for TLR7 and TLR9 in promoting MCMV recognition and immune defense in the spleen [33] . The impaired liver responses observed in 3d mice that were not apparent in TLR9 or TLR7-deficient mice [20] suggests that a level of redundancy unique to innate immunity is in place within infected tissue sites to rapidly respond to viral infection. Overall, these studies advance our understanding of the process of viral recognition in the complex liver environment and suggest that UNC93B1 is a critical intermediate factor in innate virus sensing activated by MCMV.