Ipr1 gene mediates innate immunity to tuberculosis

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Abstract
Only about one in ten individuals infected with Mycobacterium tuberculosis actually develop clinical tuberculosis. Stress, malnutrition, concomitant infections and age all influence susceptibility, but so does genetic host resistance. A gene mediating innate immunity to tuberculosis has now been identified in mice. Expression of the Intracellular pathogen resistance 1 (Ipr1) gene in macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes. The closest homologue to Ipr1 protein in humans is the nuclear body protein SP110, so the SP110 gene is a candidate to be tested for a role in tuberculosis susceptibility. An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually1. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals2,3, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis 1)4. Here we show that this locus mediates innate immunity in sst1 congenic mouse strains and identify a candidate gene, Intracellular pathogen resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages after activation and infection, but it is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data indicate that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis.