Mycobacterium tuberculosis carrying the rifampicin drug-resistance-conferring rpoB mutation H445Y is associated with suppressed immunity through type I interferons

Tuberculosis (TB) is one of the leading causes of death due to an infectious disease. The rise of multi-drug resistance (MDR) in Mycobacterium tuberculosis (Mtb), the causative agent of TB, presents a significant obstacle to TB control. While human studies report dysregulated immune responses during MDR TB, a clear understanding of the host-pathogen interactions of MDR Mtb is lacking. Here, we studied the immune responses induced by Mtb strains carrying two of the most common rifampicin drug-resistance (RDR)-conferring single-nucleotide polymorphisms (SNPs) in the RNA polymerase gene of Mtb, which accounts for nearly 90% of drug-resistance mutations found clinically in Mtb. During Mtb infection of primary human macrophages, we found that pro-inflammatory cytokine production was reduced upon infection with Mtb carrying the H445Y SNP but not the S450L SNP. Using a mouse model, we also characterized the host immune response in vivo following infection. Despite similar establishment of Mtb infection in the lung and dissemination to the peripheral organs, we show that infection with the RDR MtbrpoB-H445Y strain, but not with the rpoB-S450L strain, resulted in a suppressed lung myeloid and lymphoid immune responses through type I IFN-dependent pathways, relative to wt Mtb. This suppressed host immunity had functional consequences in limiting control of RDR Mtb strains harboring rpoB-H445Y and led to worse pathology during chronic TB disease. Collectively, our results suggest that disease pathogenesis may be associated with specific RDR mutations in Mtb, which may differentially regulate immune responses.