Roles of Pteropine Bat and Human TRIMs in Regulating Henipavirus Infection

Project Summary Bat species are the natural hosts of several emerging and re-emerging viruses including henipaviruses (HNVs). Although infection with these viruses causes high case fatality rates in humans, bats appear tolerant. Old World fruit bats in the family Pteropodidae are the natural reservoirs of HNVs, including Henda (HeV) and Nipah (NiV). HNV-pteropine bat ecological interactions are well-studied, but the mechanisms underlying the limited immunopathology in pteropine bats following HNV infection are unknown. During HNV infection in humans, the antiviral type I interferon (IFN-I) pathways are suppressed in part through the antagonism of tripartite motif proteins (TRIMs). TRIMs are involved in modulating antiviral immune responses including IFN-I production and signaling pathways. Some members of the TRIM E3 ubiquitin ligase family stimulate the IFN-I and pro-inflammatory antiviral pathways to promote viral clearance while others antagonize these pathways to limit immune-associated pathology. We have generated preliminary data that demonstrates NiV activates the IFN-I signaling pathway human cells late in infection, but IFN-I signaling remains antagonized efficiently in bat cells throughout the duration of infection. Based on this observation, we predict that bats have evolved to express a TRIM in response to NiV infection that negatively regulates the cytoplasmic RNA recognition pathway to prevent the cytopathic effects of innate immune signaling. Previously, we described the role of NiV matrix protein (NiV-M) in the degradation of human TRIM6, which inhibits TRIM6-mediated activation of IKKε- dependent IFN-I production and signaling. We found that bat TRIM6 interacts with NiV-M, but bat TRIM6 resists NiV-M mediated degradation. Due to this species-specific difference, we are interested in identifying the mechanisms that confer degradation resistance to bat TRIM6 and understanding the roles of TRIM6 during NiV infection. In this proposal, we hypothesize that NiV infection induces the expression of an immunosuppressive TRIM in bat, but not human, cells that promotes tolerance, and that species-specific differences in NiV-M-mediated TRIM6 degradation influences the course of infection. We will interrogate our hypothesis through two specific aims: (1) to identify pteropine and human TRIM orthologs differentially expressed after NiV infection and determine their roles in innate immune regulation and (2) To elucidate the mechanistic roles of human and bat TRIM6 in regulating NiV infection. Overall, the results of the proposed study will promote our understanding of the molecular regulation of pteropine bat IFN-I pathways and potentially identify factors that facilitate bats’ tolerance to HNVs. Elucidating the mechanisms that promote tolerance to HNV may serve as a basis for the development of human therapeutics.