Differenzial Activation of the NLRP3 Inflammasome by Pneumolysin Variants and Role of NLRP3 in Pneumococcal Pneumonia

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis and sepsis. While certain pneumococcal serotypes are associated with nasopharyngeal colonization, infections in patients with underlying diseases, and higher mortality when causing pneumonia, serotypes 1, 7F and 8 are predominantly found in invasive diseases that, however, show lower case-fatality rates. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia, and that some invasive pneumococcal serotypes are not recognized by this pathway. We show that humane and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1β. This IL-1β production depended on the ‘NLR family, pyrin domain containing 3’ (NLRP3) inflammasome. Serotype 1, serotype 8 and serotype 7F bacteria producing toxins with no or reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1β production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin, and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin, but is not activated by clinically important pneumococcal serotypes causing invasive disease. The study indicates that a virulence factor polymorphism can substantially affect the recognition of bacteria by the innate immune system.