Macrophage Response to Avirulent and Virulent Mycobacterium tuberculosis and Anti-TB Effects of Exosome Treatment

Tuberculosis (TB) returned as the leading cause of death from a single infectious agent in 2023. Human-macrophages and their secreted exosomes play important roles in combating invading Mycobacterium tuberculosis (Mtb). However, panoramic analysis of the underlying immune mechanism for infected macrophages, package mechanism and anti-TB effect of Mtb treated exosomes remain understood. Here we conducted comprehensive analyses of the macrophages infected with avirulent and virulent Mtb (H37Ra & H37Rv) and their exosomes through omics and phenotypic analyses. The results showed that H37Ra stimulated strong immune responses and apoptosis in macrophages to eliminate the invading Mtb, while H37Rv induced severe necrosis and immune escape for survival. Interestingly, our results suggest that macrophages kill Mtb in an interferon-gamma (IFN-γ) independent but simulative way, highlighting the central role of IFN signaling pathway in anti-TB response. Moreover, we observed selective transport of host and Mtb RNAs from macrophages to exosomes. Notably, H37Ra-treated exosomes displayed a higher anti-TB effect than H37Rv-treated exosomes due to some enriched pro-inflammation and immune escape related Mtb proteins in these two exosomes, respectively. Conclusively, our findings shed new light on the immune mechanism of macrophages in response to Mtb infection, offering a new TB treatment strategy and promising vaccine candidates.