Ipr1 gene mediates innate immunity to tuberculosis.
An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals, 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). 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.
Pan
Hui
H
Department of Immunology and Infectious Diseases, Harvard School of Public Health, 667 Huntington Avenue, Boston, Massachusetts 02115, USA.
Yan
Bo-Shiun
BS
Rojas
Mauricio
M
Shebzukhov
Yuriy V
YV
Zhou
Hongwei
H
Kobzik
Lester
L
Higgins
Darren E
DE
Daly
Mark J
MJ
Bloom
Barry R
BR
Kramnik
Igor
I
D000818:Animals; D020296:Animals, Congenic; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D018450:Disease Progression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D009336:Necrosis; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
C465035:Ifi75 protein, mouse; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D012333:RNA, Messenger; C412425:Sp110 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma