Abstract

The host cell antiviral response pathway depends heavily on manganese (Mn), but its role in defense against Mycobacterium tuberculosis ( M. tuberculosis ) infection is rarely reported. In this study, we found that, in H37Ra-infected macrophages, Mn 2+ increases the phosphorylation of stimulator of interferon genes (STING) and P65, as well as triggers the phosphorylation cascade of tumor necrosis factor (TNF) signaling pathway proteins, signal-regulated kinase (ERK), P38, and c-Jun N -terminal kinase (JNK). The activation of the TNF signaling pathway stimulated the expression of downstream inflammatory factors TNF-α, C-X-C Motif Chemokine Ligand 10(CXCL10), C C Motif Chemokine Ligand 20(CCL20), Colony Stimulating Factor 1(CSF1), Colony Stimulating Factor 2(CSF2), and Jagged Canonical Notch Ligand 1(JAG1), thereby triggering a strong inflammatory response in the cells. The excessive accumulation of TNF-α in macrophages induces necroptosis and inhibits the survival of M. tuberculosis in macrophages. When we treated macrophages with the STING inhibitor H-151, the phosphorylation of P38 was reduced, and the secretion of downstream inflammatory factors TNF-α and CXCL10, CCL20, CSF1, and CSF2 were also inhibited. Overall, this study reveals that Mn 2+ plays a crucial role in host cell defense against M. tuberculosis infection, contributes to a deeper understanding of pathogen-host interactions, and offers theoretical support for the use of Mn 2+ as a drug cofactor for the treatment of tuberculosis and the development of a new generation of drugs and vaccine adjuvants.