AUTHOR=Liu Sheng , Xie Yan , Luo Wei , Dou Yafeng , Xiong Huan , Xiao Zhen , Zhang Xiao-Lian 

TITLE=PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.00845

DOI=10.3389/fmicb.2020.00845

ISSN=1664-302X

ABSTRACT=Mycobacterium tuberculosis (M.tb) evades the surveillance of immune responses for survival in macrophages. However, the precise mechanism and toxins/proteins encoded by M.tb involved in the bacterial escape remain elusive. The function of Rv1768 protein (also referred to as PE-PGRS31, belonging to the PE_PGRS family) encoded by the region of deletion (RD) 14 in the virulent M.tb H37Rv strain, has not been reported previously. Here we was found to Rv1768 remarkably promote bacterial survival in macrophages. Compared to wild type (WT) H37Rv, Rv1768 deficient strain (H37RvΔ1768) showed significantly decreased colony-forming units (CFUs) in the lung, spleen and liver in murine M.tb infection model. The bacterial burdens of WT H37Rv in WT macrophages and C57BL/6 mice were significantly higher than that in S100A9 deficiency cells and mice, but there was no significant difference in the bacterial loads of H37RvΔRv1768. Rv1768 binds S100A9 with proline-glutamic acid (PE) domain and blocks the interaction between S100A9 and Toll-like receptor 4 (TLR4), and suppresses TLR4-myeloid differentiation factor 88 (MyD88) - nuclear factor-kappa B (NF-κB) -tumor necrosis factor α (TNF-α) signaling of macrophage. Interestingly, Rv1768 binding to S100A9 also disturbed the metabolism of arachidonic acid by activating 5-lipoxygenase (5-LO) and increasing lipotoxin A4 (LXA4), thus down-regulating cyclooxygenase-2 (Cox2) and prostaglandin E2 (PGE2) expression and promotes mycobacterial survival. Our results reveal that M.tb Rv1768 promotes mycobacterial survival in macrophage by regulation of NF-κB-TNF-α signaling and metabolism of arachidonic acid via S100A9. Disturbing the interaction between Rv1768 and S100A9 may be a potential therapeutic target for tuberculosis.