Inherently reduced expression of ASC restricts caspase-1 processing in hepatocytes and promotesPlasmodiuminfection

Abstract

AbstractInflammasome-mediated caspase-1 activation facilitates innate immune control ofPlasmodiumin the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in the hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so, or how it impactsPlasmodiumcontrol in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule ASC (apoptosis-associated speck-like protein containing CARD) is responsible for the incomplete proteolytic processing of caspase-1 in hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell-death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and resulted in better overall control ofPlasmodiuminfection in the liver mice. This however impeded the protection offered by live-attenuated anti-malarial vaccination. Tempering ASC expression in macrophages on the other hand resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.