Editors' ChoiceInnate Immunity

Candidate Gene for Tuberculosis Resistance

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Science's STKE  12 Apr 2005:
Vol. 2005, Issue 279, pp. tw135
DOI: 10.1126/stke.2792005tw135

A gene that, when mutated, appears to confer mice with susceptibility to tuberculosis has been identified and is likely to function in signaling between nuclear receptors, interferon, and pathogens. Pan et al. studied the sst1 locus (super-susceptibility to tuberculosis) in mice. Mice with mutations that caused susceptibility showed increased proliferation of Mycobacterium tuberculosis in the lungs after infection compared with that in control animals. In susceptible animals, macrophages underwent necrosis after infection, whereas those from resistant animals underwent apoptosis. The authors identified a gene, Ipr1 (intracellular pathogen resistance 1), that was expressed in resistant cells in response to infection with M. tuberculosis but not expressed in the susceptible strain. Restoration of a full-length copy of Ipr1 into the susceptible mouse strain decreased bacterial proliferation in the lungs and caused cultured macrophages to undergo apoptosis, rather than necrosis, after infection. Growth of M. tuberculosis or of another pathogen, L. monocytogenes, was suppressed in macrophages with the restored Ipr1 gene. Thus, the Ipr1 protein may help trigger innate immune responses to multiple intracellular pathogens. Exactly how it does so remains unclear, but the predicted protein product contains a domain structure indicative of a role in signaling. It contains protein-protein interaction domains, a chromatin-binding (SAND) domain, a nuclear localization signal, and a nuclear receptor-binding motif. The expression of Ipr1, and that of its human homolog (SP110), is regulated by interferons, and the SP110 protein appears to directly interact with viral proteins. Thus, the authors propose that Ipr1 may integrate signals in response to pathogens or viruses that alter gene expression and promote apoptosis of host cells. Many humans are resistant to tuberculosis, but more than two million individuals die of the disease each year.

H. Pan, B.-S. Yan, M. Rojas, Y. V. Shebzukhov, H. Zhou, L. Kobzik, D. E. Higgins, M. J. Daly, B. R. Bloom, I. Kramnik, Ipr1 gene mediates innate immunity to tuberculosis. Nature 434, 767-772 (2005). [PubMed]

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