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Tuberculosis (TB) is now the world’s second deadliest infectious killer after COVID-19. Human-macrophages and their secreted exosomes play important roles in combating invading Mtb . However, the panoramic analysis of the underlying immune mechanism for the infected macrophages, package or secretion mechanism, and anti-TB effect of Mtb treated exosomes remain poorly understood. Here we conducted comprehensive analyses of the macrophages infected with avirulent and virulent Mtb (H37Ra & H37Rv) and their secreted exosomes, collected cells and corresponding exosomes for omics and phenotypic analysis. The results showed that avirulent Mtb stimulated robust immune-responses and apoptosis in macrophages to eliminate the invading Mtb ; virulent Mtb induced severe necrosis and immune-escape for survival. The HMGB1 signaling pathway and TNFRSF1B plays important roles in the immune escape of virulent Mtb . Interestingly, our results suggest that macrophages kill Mtb in an IFN-γ independent but simulative way, highlighting the central role of IFN signaling pathway in anti-TB immune 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 some promising vaccine candidates.
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Li et al. (2024) studied this question.