Nlrp3 Increases the Host's Susceptibility to Tularemia.

() is a Gram-negative, intracellular bacterium and the causative agent of a fatal human disease known as tularemia. The CDC has classified as a Tier 1 Category A select agent based on its ease of aerosolization, low infectious dose, past use as a bioweapon, and the potential to be used as a bioterror agent. has a unique replication cycle. Upon its uptake, remains in the phagosomes for a short period and then escapes into the cytosol, where the replication occurs. is recognized by cytosolic pattern recognition receptors, Absent In Melanoma 2 (Aim2) and acht R and YD domains containing Protein (Nlrp3). The recognition of ligands by Aim2 and Nlrp3 triggers the assembly and activation of the inflammasome. The mechanism of activation of Aim2 is well established; however, how Nlrp3 inflammasome is activated in response to infection is not known. Unlike Aim2, the protective role of Nlrp3 against infection is not fully established. This study investigated the role of Nlrp3 and the potential mechanisms through which Nlrp3 exerts its detrimental effects on the host in response to infection. The results from studies demonstrate that Nlrp3 dampens NF-κB and MAPK signaling, and pro-inflammatory cytokine production, which allows replication of in infected macrophages. , Nlrp3 deficiency results in differential expression of several genes required to induce a protective immune response against respiratory tularemia. Nlrp3-deficient mice mount a stronger innate immune response, clear bacteria efficiently with minimal organ damage, and are more resistant to infection than their wild-type counterparts. Together, these results demonstrate that Nlrp3 enhances the host's susceptibility to by modulating the protective innate immune responses. Collectively, this study advances our understanding of the detrimental role of Nlrp3 in tularemia pathogenesis.