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  • The apparent lack of effect of

    2022-01-13

    The apparent lack of effect of Fas deficiency on MAV-1 replication in infected mice could be due to immunoevasion by virus inhibition of Fas activation. If that were the case, Fas deficiency would likely have minimal additional effect. HAdV infection triggers Fas internalization from the cell membrane and degradation via action of the receptor internalization and degradation (RID) complex (the HAdV E3 10.4 K and 14.5 K proteins), protecting infected Bay 11-7085 from Fas-mediated apoptosis (Elsing and Burgert, 1998, McNees et al., 2002, Shisler et al., 1997). MAV-1 replication did not affect Fas mRNA or protein levels in infected mouse fibroblasts (our unpublished data), suggesting that it is not capable of inhibiting baseline Fas function in a manner similar to HAdV. This is likely due to substantial differences between HAdV and MAV-1 E3 regions (Beard et al., 1990, Raviprakash et al., 1989). It is possible that MAV-1 inhibits Fas/FasL interactions by triggering Fas internalization without degradation, or that MAV-1 is capable of modulating baseline or IFN-γ-induced Fas expression in other cell types. Although Fas deficiency in lpr mice had no effect on viral clearance from the lungs, it was associated with decreased production of proinflammatory cytokines in the airways and lungs of infected mice. This is similar to effects of Fas deficiency on RSV-induced cytokine responses in the lungs (van den Berg et al., 2011). The cytokines that were affected by Fas deficiency are similar to those that are decreased in CD8 T cell-deficient mice compared to B6 controls during acute MAV-1 respiratory infection (Molloy et al., 2017), including IFN-γ and TNF-α. IL-1β protein and mRNA levels, which we did not measure in our work with CD8 T cell-deficient mice, were also lower in infected lpr mice than in B6 controls. The effects of Fas deficiency on MAV-1-induced airway cytokine production were not associated with corresponding decreases in apoptosis in the lungs, suggesting that they were instead mediated by non-apoptotic proinflammatory signaling pathways activated by Fas/FasL interactions (Matsumoto et al., 2007, Wajant et al., 2003, Wang et al., 2010). Fas deficiency had minimal effect on other measures of pathology that were decreased in CD8 T cell-deficient mice infected with MAV-1 such as BALF total protein concentrations and weight loss. It seems likely that CD8 T cell effector mechanisms other than Fas/FasL interactions were sufficient to cause those effects. For instance, TNF-α contributes to airway inflammation in mouse models of infection with RSV and influenza infection (DeBerge et al., 2013, Hussell et al., 2001, Peper and Van Campen, 1995, Xu et al., 2004). Residual TNF-α production in lpr mice infected with MAV-1 may have triggered other inflammatory responses. In summary, our data indicate that Fas activation contributes to airway inflammation induced during acute MAV-1 respiratory infection. Fas is not essential for control of MAV-1 replication or for clearance of MAV-1 from the lungs of infected mice, highlighting the distinction between antiviral and pro-inflammatory effects of CD8 T cells and the functional redundancy of multiple CD8 T cell effector mechanisms that likely contribute to control of MAV-1 replication. It is important to note that other types of immune cells, such as CD4 T cells, can exhibit cytotoxic activity that in some cases depends on FasL (Kotov et al., 2018). CD4 T cell depletion does not impair clearance of MAV-1 from the lungs (Molloy et al., 2017), but it is possible that CD4 T cells contribute to airway inflammation via Fas-dependent effects. FasL expression by natural killer (NK) cells contributes to their cytotoxic activity (Smyth et al., 2005). NK cell depletion or deficiency has no effect on MAV-1 replication in the brain following i.p. inoculation (Welton et al., 2008), but it is possible that NK cell-mediated Fas/FasL interactions contribute to MAV-1-induced airway inflammation following i.n. inoculation. Further understanding of the mechanisms by which CD8 T cells and other immune cells control MAV-1 infection and promote inflammation may aid in developing strategies to enhance host antiviral functions while minimizing disease.