Potential for repurposing tamoxifen for antibacterial therapy against Granulibacter bethesdensis a pathogen of Chronic Granulomatous Disease 2964

Abstract Description Granulibacter bethesdensis (Gb) is a gram-negative bacterium that causes recurrent infections linked with fatal meningitis and fulminant sepsis in patients with chronic granulomatous disease (CGD), a primary immunodeficiency with impaired production of reactive oxygen species in phagocytes. This highlights the requirement of host-directed treatment options in this infection. We have previously shown that anticancer drug tamoxifen restores antimicrobial function of CGD patients neutrophils in-vitro by inducing extracellular trap (NET) formation. Here, using a pneumonic Gb infection model of murine CGD that we have developed, we demonstrate the in-vivo protective efficacy of tamoxifen (TAM) treatment against an otherwise lethal Gb infection of CGD mice. TAM treatment improved overall survival, significantly reduced bacterial burden and improved pathology. The protective effect of tamoxifen was dependent on induction of NETs in CGD neutrophils since dismantling the NETs impaired Gb clearance in TAM-treated CGD mice. Single cell transcriptomic and flow cytometry analysis revealed that TAM treatment modified neutrophil phenotype in lungs with increased frequency of a CXCR2+ subset which constituted the NETting neutrophils in GB infected CGD mice. Our study highlights the potential of repurposing tamoxifen for treating recurrent bacterial infections by differentially modifying neutrophil phenotype characterized by enhanced NET-mediated antimicrobial defense. Funding Sources 1R21AI185850-01A1 1R01AI155582-01A1 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)