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

AuthorsSousa, Jeremy; Ca, Baltazar; Maceiras, Ana Raquel; Simoes-Costa, Luisa; Fonseca, Kaori L.; Fernandes, Ana Isabel; Ramos, Angélica; Carvalho, Teresa; Barros, Leandro; Magalhaes, Carlos; Chiner-Oms, Álvaro ; Machado, Henrique; Veiga, Maria Isabel; Singh, Albel; Pereira, Rui; Amorim, António; Vieira, Jorge; Vieira, Cristina P.; Bhatt, Apoorva; Rodrigues, Fernando; Rodrigues, Pedro N. S.; Gagneux, Sebastien; Castro, António Gil; Guimaraes, João Tiago; Bastos, Helder Novais; Osorio, Nuno S.; Comas, Iñaki ; Saraiva, Margarida
Issue Date23-Apr-2020
PublisherNature Publishing Group
CitationNature Communications 11(1):1949 (2020)
AbstractGenetic 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-1β 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-1β 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
Description14 páginas, 6 figuras. Supplementary information is available for this paper at https://doi.org/10.1038/s41467-020-15832-6. Sequence data are deposited on NCBI GEO database with the accession code GSE138580
Publisher version (URL)http://dx.doi.org/10.1038/s41467-020-15832-6
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