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.

Considering the potential of endosomal TLR signals to induce proinflammatory cytokine expression, UNC93B1 deficient 3d mice were first assessed for systemic IFN-a, IFN-c, IL-12 and TNF-a production during early infection with a moderate (5610 4 PFU) dose of MCMV. C57BL/6 (WT) and 3d mice were uninfected or MCMV-infected for 40 h or 48 h. Serum was collected at indicated time points and IFN-a, IFN-c, IL-12p70 and TNF-a were measured by enzyme-linked immunosorbent assay (ELISA). In WT mice, maximal production of IFN-a, IFN-c and IL-12p70 was detected at 40 h post-MCMV infection before declining by 48 h post-infection (Fig. 1 , A-C). In contrast, 3d mice exhibited lower serum levels of these cytokines in response to MCMV infection. Specifically, while serum IFN-a reached 13006420 pg/mL at 40 h post-MCMV infection in WT mice, IFN-a production was reduced by three-fold at this infection time point in 3d mice (4506300 pg/mL), with comparable levels maintained at 48 h post-infection (Fig. 1A) . Likewise, while average IFN-c concentrations in WT mice reached maximal levels of 5306245 pg/mL at 40 h post-MCMV infection, 3d mice failed to induce detectable levels of this cytokine (Fig. 1B) . IL-12p70 production similarly peaked at 40 h post-MCMV infection in WT mice, with levels reaching 10006600 pg/mL. 3d mice, however, produced 12-fold less IL-12p70 at this infection time point (Fig. 1C) . Serum TNF-a levels were elevated in response to MCMV infection at both 40 h and 48 h post-infection in WT mice (69610 and 63617 pg/mL, respectively, Fig. 1D ). In 3d mice, average concentrations of TNF-a were 6-fold lower than WT at 40 h and 2.5-fold lower than WT at 48 h after infection. These results indicate a requirement for endosomal TLR signals for early systemic proinflammatory cytokine production, and concur with previous reports [35] .