Abstract
Tuberculosis (TB) has returned as the leading cause of death caused by a single infectious agent in 2023. Human macrophages and their secreted exosomes play important roles in combating invading Mycobacterium tuberculosis (Mtb). However, a comprehensive understanding of the mechanisms underlying immune regulation in Mtb-infected macrophages, as well as the packaging mechanisms and anti-TB effects of Mtb-treated exosomes, is still lacking. Here, we conducted comprehensive analyses of the macrophages infected with avirulent and virulent Mtb strains (H37Ra and H37Rv) and their exosomes through omics and phenotypic approaches. The results showed that H37Ra stimulated strong immune responses and apoptosis in macrophages to eliminate 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 compensatory 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-inflammatory and immune escape-related Mtb proteins in these two exosomes, respectively. In conclusion, our findings shed new light on the immune mechanisms of macrophages in response to Mtb infection, offering a new TB treatment strategy and promising vaccine candidates.