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.

It has been established that NK cell inflammatory responses and production of IFN-c are essential to defense against MCMV in the liver [23] [24] [25] . In 3d mice, NK cell production of IFN-c in the liver was severely impaired during early MCMV infection and likely contributed to increased viral burden and liver pathology. The reduced levels of IFN-c in NK cells may reflect the deficiency of serum IL-12 seen in 3d mice. These results concur with previous reports that type I IFN regulates IL-12 production by conventional DCs and consequently the production of IFN-c by NK cells [19, 48, 56] . The defect in liver cytokine production in 3d mice is reminiscent of that reported for MyD88-deficient mice. Notably, however, MyD88-deficient mice exhibited more severe liver pathology and greater elevations in viral titers when compared to WT than we observed in 3d mice [20] . Interestingly, mice deficient in TLR7 and TLR9 exhibited decreased levels of systemic IFN-a/b and increased susceptibility to MCMV infection Data presented represent the mean 6 SD of two liver sections unless otherwise indicated. b Number of foci per 8650 mm 2 areas in day 5 infected 3d livers was significantly higher than WT at the same infection time point, p#0.04. C Nucleated cells from large areas of inflammation contained .60 nucleated cells in less defined foci, and do not include a calculation of SD. doi:10.1371/journal.pone.0039161.t001 Figure 5 . Assessment of virus-induced liver disease in 3d mice. Serum samples were collected from C57BL/6 (WT) or 3d mice that were either uninfected or infected for 3, 5, or 7 days with MCMV. Circulating levels of ALT were measured as described in Methods. Data are the combined results from three independent experiments and show the mean 6 SD (n = 6-8 mice per group). Asterisks denote p values#0.003. doi:10.1371/journal.pone.0039161.g005 [33] . Taken together, these observations further support the notion that the liver possesses compensatory mechanisms to combat viral infection in the combined absence of endosomal TLR signals. Accordingly, despite the early effects of endosomal TLR deficiency, 3d mice were able to mount robust CD8+ T cell cytokine responses. It should be noted that the 3d defect has previously been shown to impair exogenous antigen presentation, including cross presentation, which has a reported role in priming CD8+ T cell responses during MCMV infection [35] . However, we detected no overt defect in CD8+ T cell responses within the first seven days of MCMV infection in the liver. Further, examination of activation markers suggested that a similar proportion of CD8+ T cells from 3d mice were more highly activated when compared to WT (data not shown). Several studies have demonstrated the contribution of activated virus-specific CD8+ T cells to effective hepatic immunity against MCMV infection [26] [27] [28] . In addition, the normal development of adaptive responses despite impaired innate responses is well documented during MCMV infection. Studies have shown that reduced levels of type I IFN do not affect the accumulation or activation of antigenspecific CD8+ T cells in response to low or moderate MCMV inoculums [48] . Likewise, while IL-12 is critical in inducing NK cell IFN-c expression, T cell responses can occur in an IL-12independent manner [17, 18, [57] [58] [59] . NK cells have the potential to negatively regulate CD8+ T cell responses during MCMV infection [60] [61] [62] ; thus, it is probable that impaired