title: A hydrolase of trehalose dimycolate induces nutrient influx and stress sensitivity to balance intracellular growth of Mycobacterium tuberculosis.
abstract: 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 levels higher than those of 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 countereffects of TdmhMtb play an important role in balancing intracellular growth of Mtb in a manner that is directly responsive to host innate immunity.
authors: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Yong
authors: Y
authors: Yang
authors: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Kathleen
authors: K
authors: Kulka
authors: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Ronald C
authors: RC
authors: Montelaro
authors: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Todd A
authors: TA
authors: Reinhart
authors: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Seattle, WA 98109, USA.
authors: James
authors: J
authors: Sissons
authors: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Seattle, WA 98109, USA.
authors: Alan
authors: A
authors: Aderem
authors: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: ano7@pitt.edu.
authors: Anil K
authors: AK
authors: Ojha
mesh_terms: D000818:Animals; D003311:Cord Factors / Q000378:metabolism*; D003600:Cytosol / Q000382:microbiology; D017353:Gene Deletion; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000502:physiology*
chemical_list: D003311:Cord Factors; D006867:Hydrolases