Mycobacterium tuberculosis Rv1987 protein induces M2 polarization of macrophages through activating the PI3K/Akt1/mTOR signaling pathway

Mycobacterium tuberculosis (Mtb) can subvert host immune responses and survive in macrophages. Specific Mtb antigens play a critical role in this process. Rv1987, a secretory protein encoded by the gene rv1987 in the region of difference-2 (RD2) of the Mtb genome, is specifically expressed in pathogenic mycobacteria. Our previous work proved that Rv1987 induced a Th2 response in mice and enhanced mycobacterial survival in mouse lungs, but its effect on macrophages, the most important effector immune cell involved in killing Mtb, remains unclear. In this study, we used an M. smegmatis strain overexpressing Rv1987 protein to infect alveolar macrophages and the macrophage cell line RAW264.7 and analyzed the effect of Rv1987 protein on macrophage polarization. Rv1987 induced M2 polarization in macrophages both in vivo and in vitro. The bactericidal ability of these M2 polarized macrophages decreased remarkably, which resulted in the increased survival of bacteria in macrophages. Proteomics, RT-qPCR and western blotting results revealed that the PI3K/Akt1/mTOR signaling pathway was activated in Rv1987-induced M2 macrophages. Meanwhile, the SHIP molecule, a negative regulator of the PI3K/Akt1/mTOR signaling pathway, was significantly downregulated. These results suggest that Rv1987 plays an important role in modulating the host immune response and could be established as a potential drug target.