ASC and NLRP3 impair host defense during lethal pneumonia caused by serotype 3 Streptococcus pneumoniae in mice

Streptococcus (S.) pneumoniae is the most common cause of community‐acquired pneumonia. The Nod‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome, consisting of NLRP3, ASC (the adaptor apoptosis‐associated speck‐like protein containing a CARD) and caspase‐1, has been implicated in protective immunity during pneumonia induced by high doses of S. pneumoniae serotype 2. Here we investigated the role of the NLRP3 inflammasome in the host response during lethal airway infection with a low dose of serotype 3 S. pneumoniae. Mice were euthanized at predefined endpoints for analysis or observed in survival studies. In additional studies, Tlr2−/−/Tlr4−/− mice and Myd88−/− mice incapable of Toll‐like receptor signaling were studied. In stark contrast with existing literature, both Nlrp3−/− and Asc−/− mice showed a strongly improved host defense, as reflected by a markedly reduced mortality rate accompanied by diminished bacterial growth and dissemination. Host defense was unaltered in Tlr2−/−/Tlr4−/− mice and Myd88−/− mice. These results show that the NLRP3 inflammasome impairs host defense during lethal pneumonia caused by serotype 3 S. pneumoniae. Our findings challenge the current paradigm that proximal innate detection systems are indispensable for an adequate host immune response against bacteria. Pneumococcal pneumonia is a common cause of sepsis. In this study we demonstrate that the inflammasome can have a detrimental role during pneumonia, while TLR‐dependent signaling was not significant for the host response. These findings challenge previous reports about the host immune response against bacteria.