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

Tuberculosis (TB) remains a deadly disease. The genetic diversity of Mycobacterium tuberculosis was neglected in the past, but is increasingly recognized as a determinant of immune responses and clinical outcomes of TB. However, how this bacterial diversity orchestrates immune responses to direct differences in TB severity remains unknown. We studied 681 patients with pulmonary TB and found that phylogenetically related M. tuberculosis isolates from cases with mild disease induced robust cytokine responses in macrophages. In contrast, isolates associated with severe TB cases failed to do so. Using representative isolates, we show that M. tuberculosis inducing a low cytokine response in macrophages also diminished activation of cytosolic surveillance systems, including cGAS and the inflammasome, suggesting a novel mechanism of immune escape. Isolates exhibiting this evasion strategy carried mutations in various components of the ESX-I secretion system. We conclude that host interactions with different M. tuberculosis strains results in variable TB severity. AmpliSeq Transcriptome was performed in bone marrow-derived macrophages infected with two Mtb clinical isolates to compare the induced responses. Non-infected cells were also included as control.