Mechanism Of Mycobacterium Tuberculosis Rv1987 Protein Regulating Host Macrophage Polarization

The emergence of multidrug-resistant TB(MDR-TB)is a serious challenge to tuberculosis(TB)control.Therefore,there is an urgent need to develop new targets for the diagnosis and treatment of TB.Previous Mtb antigens screening assay identified several potential antigens that provide better sensitivity and accuracy,Rv1987 protein is considered as a potential diagnostic and vaccine development target for TB.Mtb Rv1987,encoded by the gene Rv1987 in the region of difference-2(RD2),is a putative chitinase secretory protein.Several studies have shown that Rv1987 promotes the production of IL-4 and modulates host immune response towards Th2 profile.However,the detailed molecular mechanism of Rv1987 involved in the regulation of host cells remain largely unclear.Previous studies have shown that Th1/Th2 inflammatory response in T cells can be regulated by M1-or M2-type macrophages.Macrophages are one of the primary intracellular niches for Mtb survival and replication in the host.We speculate that Rv1987 may regulate the polarization of host macrophages.In the mycobacteria-infection assays,we found that Rv1987 upregulated the levels of IL-10 and Arg,and the expression of CD206 on the surface of macrophages in a manner that was dependent on the activation of Wnt/?-catenin signaling pathway.Furthermore,Rv1987-interacting proteins in host were rescreened using Rv1987 as a bait by the yeast two-hybrid assay.We determined that Calcyclin-binding protein/Siah-1Interacting Protein(Cacybp/SIP)interacted with Rv1987.As reported,Cacybp/SIP plays an important role in the degradation of ?-catenin.In this study,we further found that Rv1987 inhibits the ubiquitination of ?-catenin and stabilized ?-catenin protein,ultimately leading to promotion of polarization of M2-type macrophage as well as the survival of Mtb.Taken together,our study reveals that Rv1987 can specifically bind Cacybp/SIP,promote polarization of M2-type macrophage and the survival of tuberculosis through activating Wnt/?-catenin signaling pathway.Our findings reveal novel sights into the intricate interactions between Mtb and its host,thus provide a potential TB treatment by targeting Rv1987.Our study indicate that macrophage polarization palys an important role in host defense against TB and provide a novel target for the development of TB vaccines and drugs.