CYBB-Mediated Ferroptosis Associated with Immunosuppression in Mycobacterium leprae–Infected Monocyte-Derived Macrophages

Mycobacterium leprae- infected macrophages preferentially exhibit the regulatory M2 phenotype in vitro, which help the immune escape unabated growth of M. leprae in host cells. The mechanism that triggers macrophages polarization is still unknown. Herein, we performed single-cell RNA- sequencing (scRNA- seq) to determine the initial responses of human monocyte-derived macrophages (MDMs) against M. leprae infection of 4 healthy individuals and found an increase in a major alternative-activated macrophage type that overexpressed NEAT1, CCL2 and CD163. Importantly, further functional analysis showed that ferroptosis was positively correlated with M2 polarization of macrophages and in vitro experiments have shown that inhibition of ferroptosis promote the survival of M. leprae within macrophages. In addition, further joint analysis of our results with muti sequencing data from leprosy patients and in vitro validation identified that Cytochrome B-245 Beta Chain (CYBB) was the pivotal molecule for ferroptosis which could promote the M2 polarization of M. leprae infected macrophages, resulting to the immune escape and unabated growth of pathogenic bacteria. Overall, our results suggest that M. leprae facilitated its survival by inducing CYBB-mediated macrophage ferroptosis leading to its alternative activation and might reveal the potential for new therapeutic strategy of leprosy.