Targeting TMEM176B Controls Inflammasome-dependent T cell Dysfunction in Coronavirus Infection

DUHALDE VEGA M,; OLIVERA, DANIELA

Congreso; FOCIS 2021 Virtual Anual Meeting; 2021

The NLRP3 inflammasome/IL-1β pathway has been shown to play a key immunopathogenic role in COVID-19. However, the mechanisms by which inflammasomesare contolled and lead to severe disease and death in coronavirus disease are largely unknown. We speculated that the NLRP3 inflammasome inhibitor, TMEM176B, may control coronavirus-induced pathogenesis. Using a mouse coronavirus infection model (MHV-A59), we show that Tmem176b is a key host player that controls viral infection by inhibiting inflammasome activation.In vivo, Tmem176b-/- mice showed worse survival and increased viral load upon MHV infection as compared to WT and Tmem176b-/-Casp1-/- animals.IL-1β blockade significantly protected Tmem176b-/- mice in a CD8-dependent manner. Accordingly, MHV-A59-infected Tmem176b-/- animals had fewer total and MHV-A59-specific CD8+ T cells and decreased in vivo CD8-dependent cytotoxicity against MHV-A59 antigens.PD-1 blockade significantly improved the survival of MHV-A59- infected Tmem176b-/- mice.We then found that the flavonoid isoquercetin ehnhanced Tmem176b activity in a dose-dependent manner and inhibited MHV-A59-induced inflammasome activation in mouse dendritic cells. In vivo, isoquercitin significantly diminished MHV-A59 viral load. TMEM176B expression was increased in peripheral blood monocytes from mild COVID-19 in comparison to severe patientsIsoquercitin inhibitedsevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced inflammasome activation in human monocytesin vitro. Moreover, isoquercitin hinders coronavirus-induced PD-1 expression in vitro in human CD4+ and CD8+ T cells. Thus, targeting TMEM176B with isoquercitin could control inflammasome activation and immune dysfunction triggered by coronavirus infection. Ongoing experiments are trying to determine whether isoquercitin can control SARS-CoV2 infectionin vivo.