Inflammasome Signaling and Bacterial Infections

Manoranjan Sahoo, Louis Lantier, Fabio Re, Sahoo, Manoranjan, Lantier, Louis, Re, Fabio

Burkholderia pseudomallei is a Gram-negative flagellate bacterium that causes melioidosis, a disease endemic to Southeast Asia and other tropical regions. Following infection of macrophages and other non-phagocytic cell types, B. pseudomallei or B. thailandensis (a related species that causes disease in mice but not humans) are able to escape the phagosome and replicate in the host cell cytoplasm. Resistance to infection with Burkholderia is dependent on the Nlrp3 and Nlrc4 inflammasomes and the non-canonical caspase-11 inflammasome. Nlrc4 mediates protection through induction of pyroptosis in the early phase of infection. As the infection progresses and as IL-18-dependent IFNγ production increases, caspase-11-dependent pyroptosis acquires a preponderant protective role. Production of IL-1β and IL-18 during infection is primarily mediated by Nlrp3. IL-18 is essential for survival because of its ability to induce IFNγ production, which in turn activates macrophage microbicidal functions and primes for caspase-11 expression. In contrast, during melioidosis, IL-1β has deleterious effects due to excessive recruitment of neutrophils to the lung and consequent tissue damage.