A hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of Mycobacterium tuberculosis

Summary Chronic tuberculosis in an immunocompetent host is a consequence of the delicately balanced growth of Mycobacterium tuberculosis (Mtb) in the face of host defense mechanisms. We identify an Mtb enzyme (Tdmh Mtb ) that hydrolyzes the mycobacterial glycolipid trehalose dimycolate and plays a critical role in balancing the intracellular growth of the pathogen. Tdmh Mtb is induced under nutrient-limiting conditions and remodels the Mtb envelope to increase nutrient influx but concomitantly sensitizes Mtb to stresses encountered in the host. Consistent with this, a Δtdmh Mtb mutant is more resilient to stress and grows to levels higher than those of wild-type in immunocompetent mice. By contrast, mutant growth is retarded in MyD88 −/− mice, indicating that Tdmh Mtb provides a growth advantage to intracellular Mtb in an immunocompromised host. Thus, the effects and countereffects of Tdmh Mtb play an important role in balancing intracellular growth of Mtb in a manner that is directly responsive to host innate immunity.