Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1ß production

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.This work was financed by FCT-Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Inovação grant POCI-01-0145-FEDER-028955 (to M.S.) and by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013, to M.I.V., F.R., A.G.C., and N.S.O.). I.C. acknowledges the support of Ministerio de Ciencia, Innovación y Universidades (SAF2016-77346-R) and the European Research Council (638553-TB-ACCELERATE). H.N.B. acknowledges the support of Bolsa D. Manuel de Mello and of the Portuguese Society for Pneumology; A.B. and M.S. were also recipients of an International Exchanges Grant from the Royal Society. J.S. is funded by a research fellow NORTE-01-0145-FEDER-000012; B.C. and K.L.F. are funded by FCT Ph.D scholarships SFRH/BD/114403/ 2016 and SFRH/BD/114405/2016, respectively; M.I.V. is funded by FCT through DL 57/ 2016 (CRP) and MS through Estimulo Individual ao Emprego Científico. We thank the excellent support from the i3S scientific platforms, namely Animal facility, Advanced Light Microscopy, and BioSciences Screening, member of the national infrastructure PPBI-Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122) and Genomics (GenCore) part of the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT)