Mycobacterium tuberculosis Rv2653 Protein Promotes Inflammation Response by Enhancing Glycolysis.

Abstract

Mycobacterium tuberculosis (M.tb) infection causes the communicable disease tuberculosis (TB), a major disease and one of the leading causes of death worldwide. The protein encoded by the region of deletion (RD) in M.tb mediates the pathogenic properties of M.tb by inducing an inflammatory response or disrupting host cell metabolism. We cloned and purified the Rv2653 protein from RD13 to explore its regulatory effects on host macrophages. We found that Rv2653 promoted glycolysis and upregulated the expression of key glycolytic enzymes, namely, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) in human leukemia monocytic (THP1) cells. Furthermore, the induction of glycolysis by Rv2653 contributes to the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome. Rv2653 activated the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, and the mTORC1 inhibitor NR1 blocked Rv2653-induced HK2, LDHA, and NLRP3 expression. siRNA interfering with HK2 or LDHA significantly inhibited the activation of NLRP3 inflammasome by Rv2653, blocked Rv2653-triggered inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), and nitric oxide (NO), and promoted the survival of Bacillus Calmette-Guerin (BCG) in THP1 cells. Overall, Rv2653 promoted glycolysis by activating the mTORC1 signaling pathway, activating the NLRP3 inflammasome, and releasing inflammatory factors, ultimately inhibiting the intracellular survival of BCG in THP1 cells. Therefore, we revealed that anti-M.tb immune mechanisms induced by Rv2653 contribute to the development of new anti-TB strategies.