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.

Having observed a reduction in the level of proinflammatory cytokines in the serum of 3d mice, cytokine responses in liver cells from 3d mice infected with MCMV were evaluated to address the impact of endosomal TLR signaling in a localized tissue site of infection. The best characterized liver cytokine responses are IFNa and IFN-c [20, 21, 36] . Therefore, to determine whether combined endosomal TLR signaling contributes to the production of these cytokines during MCMV infection, IFN-a and IFN-c in liver homogenates and in individual cell populations were measured in WT and 3d mice uninfected or infected with MCMV for 40 h and 48 h. As shown in Fig. 2A , WT mice displayed fourfold higher levels of IFN-a than 3d mice at 40 h post-infection, with increased levels still evident at 48 h following infection. Since pDCs expressing the marker PDCA-1 have been shown to produce the majority of liver IFN-a at 40 h post-MCMV infection [20] , this cell type was examined in WT and 3d livers during early infection. There was evidence of pDC accumulation in the livers of both WT and 3d mice (Fig. 2B ). However, liver pDCs from 3d mice were impaired in their ability to express IFN-a. There were 4-fold fewer PDCA-1+ pDCs expressing intracellular IFN-a at 40 h, and 3-fold fewer at 48 h post-infection, in 3d mice as compared to WT (Fig. 2C ). This trend was also reflected in the proportion of PDCA-1+ IFN-a+ pDCs at 40 h and 48 h after infection in 3d mice (0.8%60.4% and 2%61%) compared with WT (2%61% and 6%61%).