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Identification of nitric oxide synthase as a protective locus against tuberculosis.

TitleIdentification of nitric oxide synthase as a protective locus against tuberculosis.
Publication TypeJournal Article
Year of Publication1997
AuthorsMacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan C
JournalProc Natl Acad Sci U S A
Volume94
Issue10
Pagination5243-8
Date Published1997 May 13
ISSN0027-8424
KeywordsAlleles, Animals, Carrier Proteins, Cation Transport Proteins, Crosses, Genetic, Disease Susceptibility, Exons, Female, Genotype, Glucocorticoids, Haplotypes, Heterozygote, Homozygote, Immunity, Innate, Immunosuppression, Isoenzymes, Lung, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Mycobacterium tuberculosis, Nitric Oxide Synthase, Polymerase Chain Reaction, Polymorphism, Genetic, Tuberculosis
Abstract

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID9144222
PubMed Central IDPMC24663
Grant ListAI34543 / AI / NIAID NIH HHS / United States
HL51960 / HL / NHLBI NIH HHS / United States
HL51967 / HL / NHLBI NIH HHS / United States

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