A Mycobacterium tuberculosis secreted virulence factor Rv1435c/hsr1 disrupts host snRNP biogenesis

Transcriptional adaptation drives the host responses to Mycobacterium tuberculosis (Mtb) infection. However, Mtb alters host RNA splicing to quench host antibacterial responses, the mechanism for which remains unknown. Here, we report a mechanism whereby a secreted Mtb protein interferes with the biogenesis of key spliceosomal components. A high-throughput yeast-2-hybrid screen identified several Mtb-secreted proteins interacting with the host RNA splicing factors (SFs). Through custom-designed in-cell assays, we show that one of those proteins, Rv1435c/hsr1 (host splicing regulator 1), targets specific exon-skipping events. The Mtb Rv14345c/hsr1 facilitates direct interaction between Mtb phagosomes and U5 snRNA and SNRPF, key components of the snRNPs. Genetic deletion of Rv1435c/hsr1 reverses the specific exon-skipping events caused by WT Mtb infection. The Δhsr1 strain shows compromised growth during ex vivo infection in macrophages and in vivo infection in mice. Tissue sections from the WT Mtb or Δhsr1-infected mice showed significant hsr1-dependent SNRPF staining, a phenomenon also noted in the human intestinal tuberculosis (ITB) biopsies. Thus, hsr1 is a virulence factor that disrupts host snRNP biogenesis for pathogenesis. The splicing regulators from the host and pathogen are novel targets for antituberculosis therapy.