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Ipr1 gene mediates innate immunity to tuberculosis

Abstract

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.

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Figure 1: The sst1 locus mediates innate immunity to tuberculosis.
Figure 2: Identification of the sst1 candidate gene.
Figure 3: Lack of Ipr1 expression in the C3HeB/FeJ substrain correlates with its extreme susceptibility to M. tuberculosis infection.
Figure 4: Expression of the Ipr1 transgene in the sst1S macrophages confers resistance to intracellular pathogens M. tuberculosis and L. monocytogenes.

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Acknowledgements

We thank I. Breiterene, K. Vasquez, K. Sigrist and C. Mottley for technical assistance, and R. Kucherlapati, P. Demant, W. F. Dietrich, S. Agoulnik and D. Bloch for discussions and support throughout the project. This work was supported by the National Institutes of Health.

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Correspondence to Igor Kramnik.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

Tuberculosis lung lesions in the sst1R and the sst1S congenic mouse strains after aerosol infection with MTB (PDF 2086 kb)

Supplementary Figure S2

MTB growth in the organs of the sst1 congenic mouse strains and bone marrow chimeras after systemic i.v. infection (PDF 62 kb)

Supplementary Figure S3

Analysis of the sst1 minimal region (PDF 548 kb)

Supplementary Figure Legends

Legends to accompany the above Supplementary Figures (DOC 36 kb)

Supplementary Table S1

List of all known and predicted genes within the sst1 minimal region (DOC 75 kb)

Supplementary Data

Identification of a candidate gene within the sst1 locus (DOC 52 kb)

Supplementary Methods

Additional details of methods used in this study. (DOC 52 kb)

Supplementary Notes

Nramp1 alleles of the inbred mouse strains used in the study and TUNEL staining of the tuberculosis lung lesions of the sst1R and sst1S congenic mice (PDF 705 kb)

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Pan, H., Yan, BS., Rojas, M. et al. Ipr1 gene mediates innate immunity to tuberculosis. Nature 434, 767–772 (2005). https://doi.org/10.1038/nature03419

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  • DOI: https://doi.org/10.1038/nature03419

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