1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, 667 Huntington Avenue, Boston, Massachusetts 02115, USA
2. Physiology Program, Department of Environmental Health, Harvard School of Public Health, 667 Huntington Avenue, Boston, Massachusetts 02115, USA
3. Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
4. Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
6. These authors contributed equally to this work
7. Present address: Department of Molecular Immunology, A. N. Belozersky Institute of Physical and Chemical Biology, Moscow State University, Vorobjovy Gory, Moscow, 119899, Russia

Correspondence to: Igor Kramnik¹ Correspondence and requests for materials should be addressed to I.K. (Email: ikramnik@hsph.harvard.edu).
The Ipr1 sequence has been deposited in GenBank under accession number AY845948.

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 animals^{2, 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.

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