XIAP-associated factor 1 protects against viral-induced neuropathogenesis.

XIAP-associated factor 1 (XAF1) is a proapoptotic protein known to be involved in tumor suppression and regression whose gene expression has been reported to be dysregulated in a wide variety of tumor malignancies by different molecular mechanisms. Using a sterile alpha and TIR motif containing 1 (SARM1) knockout mouse model, we previously showed that XAF1 could be a candidate gene for protection against neurotropic virus infection. Here, using a CRISPR-knockout XAF1 mouse model, we show that XAF1 knockout mice are more susceptible to disease after VSV infection, a well-known neurotropic virus in mice. Interestingly, VSV-increased sensitivity in XAF1 knockout mice was not accompanied by differences in viral replication in the central nervous system (CNS). Nevertheless, infection of XAF1 knockout mice resulted in an increased pro-inflammatory response and immune cell infiltration into the CNS compared to that in wild-type mice. Similarly, XAF1 knockout mice showed slight increase to disease after infection with a different neurotropic virus, West Nile Virus (WNV). However, no differences in viral disease due to the absence of XAF1 were found upon infection with a respiratory virus such as influenza A virus (IAV). In vitro, XAF1-deficient cells showed a significant increase in interferon-stimulated genes (ISGs) expression upon stimulation with IFN and with different PAMPs, such as Poly(I:C), HT-DNA and LPS. Consistently, ectopic overexpression of XAF1 decreased IFN-signaling in a dose-dependent manner. Altogether, the data presented here suggest that the host factor XAF1 has a protective role in viral-induced neuropathogenesis due to excessive IFN responses. Author summaryWe previously identified XIAP-associated factor 1 (XAF1) as a candidate cell factor involved in viral phenotypes attributed to SARM1 deficiency. Even though the role of this factor has been studied in the cancer field as a proapoptotic tumor suppressor, its relevance in the context of viral infections has remained unclear. Here, we show that XAF1-deficient mice show increased susceptibility upon neurotropic virus infection and augmented levels of proinflammatory cytokines. We observe higher immune cell infiltration into the brain and disease exacerbation upon infection in mice lacking XAF1. This increased pathology is restricted to the brain, since no morbidity was observed upon infection with a respiratory virus, such as influenza virus. Gene expression analysis unveiled an unbalanced immune response in XAF1-deficient mice resulting in an elevated proinflammatory response and diminished capacity to restore homeostasis. Our data demonstrates the protective capacity of XAF1 and provides new insights into the host response against virus infections.