A Hydrolase of Trehalose Dimycolate Induces Nutrient Influx and Stress Sensitivity to Balance Intracellular Growth of Mycobacterium tuberculosis

Abstract

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 (TdmhMtb) that hydrolyzes the mycobacterial glycolipid trehalose dimycolate and plays a critical role in balancing the intracellular growth of the pathogen. TdmhMtb 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 ΔtdmhMtb mutant is more resilient to stress and grows to higher levels than wild-type in immunocompetent mice. By contrast, mutant growth is retarded in MyD88−/− mice indicating that TdmhMtb provides a growth advantage to intracellular Mtb in an immunocompromised host. Thus, the effects and counter-effects of TdmhMtb play an important role in balancing intracellular growth of Mtb in a manner that is directly responsive to host innate immunity.

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response

“…Thus, TDM may be one source of FM. In fact, Yang et al 22 estimated that about 20% of FM in the cell wall may be derived from the hydrolysis of TDM.…”

“…Among seven cutinaselike proteins with esterase activities previously described in M. tuberculosis, the authors suggested that Rv3452 is a possible TDM hydrolase in M. tuberculosis because of its closest relatedness to Msmeg_1529 21 . Indeed, it was shown later that Rv3452, and also Rv3451, share > 50% amino acid similarity with Msmeg_1529 22 . Experiments revealed that Rv3451 is the primary TDM hydrolase in M. tuberculosis 22 .…”

“…Indeed, it was shown later that Rv3452, and also Rv3451, share > 50% amino acid similarity with Msmeg_1529 22 . Experiments revealed that Rv3451 is the primary TDM hydrolase in M. tuberculosis 22 . Thus, TDM may be one source of FM.…”

“…However, it has been since suggested that some FMs in the bacterial cell wall are derived from the hydrolysis of TDM 22 and may interact with host cells to induce some type of innate immune response.…”

“…At that infection stage, (1) the capacity of M. tuberculosis to induce pro-inflammatory response is diminished; (2) the bacterium becomes drug tolerant 22 ; and (3) nutrient uptake increases as the host imposes bacterial starvation 22 .…”