Host-specific immune responses against Leptospira spp 3638

Abstract Description Leptospira interrogans is the major causative agent of leptospirosis. Rodents are considered the most important reservoir of Leptospira. Infected rodents are asymptomatic carriers in which bacteria colonize the kidneys and are shed in the urine. Leptospira also infects a variety of other mammals including humans. Humans are incidental hosts but can develop fulminant disease which can prove fatal. The immune response to Leptospira spp. remains poorly defined. Leptospira can induce an IL-1β response via NLRP3 inflammasome activation. However, compared to other bacteria, L. interrogans triggers a relatively weak IL-1β response in mouse macrophages. In contrast, L. interrogans induces a robust IL-1β response in human monocytes. To investigate this, we utilized a mouse model with a mutation in NLRP3, associated with human cryopyrin-associated periodic syndrome, which results in NLRP3 hyperactivation. We observed a pronounced IL-1β response in NLRP3A350V/+ mouse macrophages upon infection with L. interrogans. An intraperitoneal infection of NLRP3A350V/+ mice with L. interrogans also resulted in increased mortality compared to wild-type mice. Moreover, a subcutaneous infection of NLRP3A350V/+ mice resulted in diminished kidney colonization, suggesting that a robust NLRP3 response may limit bacterial persistence in the kidney. These findings offer insights into why rodents serve as reservoir hosts for L. interrogans, while humans are more susceptible to severe disease. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)