Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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.
Cell Host Microbe. 2014 Feb 12;15(2):153-63. doi: 10.1016/j.chom.2014.01.008.
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.
在免疫功能正常的宿主中，慢性结核病是结核分枝杆菌（Mycobacterium tuberculosis，Mtb）在宿主防御机制面前微妙地平衡生长的结果。我们鉴定出一种 Mtb 酶（TdmhMtb），它能水解分枝杆菌糖脂海藻糖二没食子酸酯，并在平衡病原体的细胞内生长方面发挥关键作用。TdmhMtb 在营养有限的条件下被诱导，并重塑 Mtb 包膜以增加营养物质的流入，但同时使 Mtb 对宿主中遇到的应激敏感。与此一致的是，ΔtdmhMtb 突变体对压力更具弹性，在免疫功能正常的小鼠中生长水平高于野生型。相比之下，突变体的生长在 MyD88(-/-) 小鼠中受到抑制，表明 TdmhMtb 在免疫功能低下的宿主中为细胞内 Mtb 提供了生长优势。因此，TdmhMtb 的作用和反作用在以直接响应宿主先天免疫的方式平衡 Mtb 细胞内生长方面发挥着重要作用。
