Fatty Acyl-CoA Synthetase D33 Promotes Survival in Hostile Extracellular and Intracellular Microenvironments in the Host.

Tuberculosis, caused by (), remains a significant global health challenge. The survival of in hostile extracellular and intracellular microenvironments is crucial for its pathogenicity. In this study, we discovered a (BCG) mutant B1033 that potentially affected mycobacterium pathogenicity. This mutant contained an insertion mutation gene, D33, which is involved in lipid metabolism; however, its direct role in regulating infection is not well understood. Here, we found that the absence of D reduced BCG adhesion and invasion into human pulmonary alveolar epithelial cells and increased the permeability of the mycobacterial cell wall, allowing to survive in the low pH and membrane pressure extracellular microenvironment of the host cells. The absence of D also inhibited the survival of BCG in macrophages by promoting the release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumors necrosis factor-α, through the mitogen-activated protein kinase p38 signaling pathway. Overall, these findings provide new insights into mechanisms to evade host defenses and might contribute to identifying potential therapeutic and vaccine targets for tuberculosis prevention.