Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis

•Gain-of-function NLRP3 rs10754558 and CTSB rs8898 contribute to protection against the development of active pulmonary TB•Loss-of-function P2X7 rs2230911 is associated to increased susceptibility to active pulmonary TB also in Brazilian Amazon•Increased activation of NLRP3-inflammasome is beneficial against the development of active pulmonary TB

Tuberculosis (TB) continues to be a major public health problem. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) but remains asymptomatic (latent TB) and only 5% to 10% of these latent individuals will develop active pulmonary TB. Factors affecting the balance between latent and active TB are mostly unknown, even if host genome has been shown to contribute to the outcome of Mtb response. Acute inflammation and Th1 response are important in the early clearance of the bacteria as it was emphasized by the association between immune genes (i.e.: HLA, IFNG, TNF, NRPAM1, IL10) variants and the development of active pulmonary TB.Recently, the role of the inflammasome in experimental TB has been demonstrated, however, to our knowledge, no data still exist about the contribution of inflammasome genetics to Mtb susceptibility and/or to the development of active TB.For this reason, selected polymorphisms in inflammasome genes were analysed in a case/control cohort of individuals with active pulmonary TB from an endemic area of Brazil Amazon.Our data evidence the novel association between polymorphisms in NLRP3-inflammasome encoding genes and active pulmonary TB, and replicated the association between P2X7 and TB observed in other populations.These results emphasize the role of NLRP3-inflammasome also in human TB, and contribute to our knowledge about pathways involved in the development of active TB, even if deeper investigation are needed to fully elucidate the role of the complex in Mtb infection.

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