A Mycobacterium tuberculosis secreted virulence factor disrupts host snRNP biogenesis

We earlier reported that Mycobacterium tuberculosis (Mtb) alters host RNA splicing to help its intracellular growth. Here, we report an unprecedented mechanism whereby a secreted virulence factor from Mtb interferes with the biogenesis of key spliceosomal components, causing an altered RNA splicing pattern. A high-throughput yeast-2-hybrid screen identified several Mtb-secreted proteins that can interact with the host RNA splicing factors (SFs). Through custom-designed in-cell assays, we show that one of those proteins, Rv1435c, targets specific exon-skipping events to alter RNA splicing. We show that Rv14345c or host splicing regulator 1 (hsr1) facilitates direct interaction between Mtb phagosomes and U5 snRNA and SNRPF, key components of the snRNPs. Genetic deletion of hsr1 reverses the specific exon-skipping events caused by WT Mtb infection. The{Delta} hsr1 strain shows compromised growth during ex vivo infection in the macrophages and in vivo infection in the mice. Tissue sections from the WT Mtb or{Delta} hsr1-infected mice showed significant hsr1-dependent SNRPF staining, a phenomenon also noted in the human intestinal tuberculosis (ITB) biopsies. We infer that hsr1 is a virulence factor which alters RNA splicing by interacting with U5snRNA and SNRPF. The splicing regulators from the host and pathogen are novel targets for anti-tuberculosis therapy.