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Tuberculosis (TB) is responsible for death of nearly two million people in the world annually. Upon infection,  Mycobacterium tuberculosis  ( Mtb)  causes formation of granuloma where the pathogen goes into dormant state and can live for decades before resuscitation to develop active disease when the immune system of the host is weakened and/or suppressed. In an attempt to better understand host-pathogen interactions, several groups have been developing  in vitro  models of human tuberculosis granuloma. However, to date, an  in vitro  granuloma model in which  Mtb  goes into dormancy and can subsequently resuscitate under conditions that mimic weakening of the immune system has not been reported. We describe the development of a biomimetic  in vitro  model of human tuberculosis granuloma using human primary leukocytes, in which the  Mtb  exhibited characteristics of dormant mycobacteria as demonstrated by (1) loss of acid-fastness, (2) accumulation of lipid bodies (3) development of rifampicin-tolerance and (4) gene expression changes. Further, when these micro granulomas were treated with immunosuppressant anti-tumor necrosis factor-alpha monoclonal antibodies (anti-TNFα mAbs), resuscitation of  Mtb  was observed as has been found in humans. In this human  in vitro  granuloma model triacylglycerol synthase 1deletion mutant (Δ tgs1 ) with impaired ability to accumulate triacylglycerides (TG), but not the complemented mutant, could not go into dormancy. Deletion mutant of  lipY , with compromised ability to mobilize the stored TG, but not the complemented mutant, was unable to come out of dormancy upon treatment with anti-TNFα mAbs. In conclusion, we have developed an  in vitro  human tuberculosis granuloma model that largely exhibits functional features of dormancy and resuscitation observed in human tuberculosis.

Human Granuloma In Vitro Model, for TB Dormancy and Resuscitation