Abstract
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-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.
Highlights
Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB)
To investigate whether M. tuberculosis-associated determinants may contribute to the pathogenesis of TB through the manipulation of host immune responses, we started by stratifying TB severity in a fully characterized population of TB patients[10]
Across a range of different host cells, M. tuberculosis isolates recovered from severe TB cases induced lower cytokine responses as compared to those recovered from mild TB patients
Summary
Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). 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. During its parallel evolution with the human host[3], M. tuberculosis developed important immune evasion mechanisms, including virulence factors aimed at preventing elimination by macrophages[4], and strategies to modulate T-cell responses to favor transmission[5]. One can expect a relevant role for both host and pathogen diversity in disease establishment and transmission, through the modulation of host immune responses. This study contributes to our understanding of the modulation of host immunity to TB, with the potential to inform the design of hostdirected and pathogen-directed therapies for this devastating disease
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