Granulysin antimicrobial activity promotes dormancy in<i>Mycobacterium tuberculosis</i>

Human tuberculosis (TB) caused byMycobacterium tuberculosis(Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain or exacerbate an infection. Containment is exploited byMtbas a hideout to persist in a dormant, antibiotic-tolerant state only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response drivingMtbpersistence remain elusive. We here combined anex vivogranuloma model with peripheral blood mononuclear cell (PBMC) specimens from TB patients and a high-dimensional mass cytometry (CyTOF) approach to shed light on the immune factors promptingMtbdormancy. Compared to healthy controls, patient-derivedex vivogranulomas rapidly forceMtbto adopt a dormant-like state; an observation that correlates with the presence of activated innate (-like) cytotoxic lymphocytes. We further demonstrate thatMtbdormancy is induced by direct exposure to granulysin, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.