Identification of nitric oxide synthase as a protective locus against tuberculosis.
Mutagenesis of the host immune system has helped identify response pathways necessary to combat tuberculosis. Several such pathways may function as activators of a common protective gene: inducible nitric oxide synthase (NOS2). Here we provide direct evidence for this gene controlling primary Mycobacterium tuberculosis infection using mice homozygous for a disrupted NOS2 allele. NOS2(-/-) mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowed Mycobacterium tuberculosis to replicate faster in the lungs than reported for other gene-deficient hosts. Susceptibility appeared to be independent of the only known naturally inherited antimicrobial locus, NRAMP1. Progression of chronic tuberculosis in wild-type mice was accelerated by specifically inhibiting NOS2 via administration of N6-(1-iminoethyl)-L-lysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.
MacMicking
J D
JD
Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021, USA.
North
R J
RJ
LaCourse
R
R
Mudgett
J S
JS
Shah
S K
SK
Nathan
C F
CF
D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D027682:Cation Transport Proteins; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D005091:Exons; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D007113:Immunity, Innate / Q000235:genetics*; D007165:Immunosuppression Therapy; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000099173:Natural Resistance-associated Macrophage Protein 1
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D005938:Glucocorticoids; D007527:Isoenzymes; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase; D000099173:Natural Resistance-associated Macrophage Protein 1