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 Mycoba...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-05, Vol.94 (10), p.5243-5248
Main Authors: MacMicking, John D., North, Robert J., LaCourse, Ron, Mudgett, John S., Shah, Shrenik K., Nathan, Carl F.
Format: Article
Language:English
Subjects:
Alleles
Animals
Biological Sciences
Carrier Proteins - biosynthesis
Carrier Proteins - genetics
Cation Transport Proteins
Crosses, Genetic
Disease Susceptibility
Exons
Female
Genes
Genetic loci
Genotype
Glucocorticoids - pharmacology
Haplotypes
Heterozygote
Homozygote
Immunity (Disease)
Immunity, Innate - genetics
Immunosuppression Therapy
Infections
Isoenzymes - biosynthesis
Isoenzymes - deficiency
Isoenzymes - genetics
Lung - microbiology
Lung - pathology
Lungs
Macrophages
Male
Medical research
Membrane Proteins - biosynthesis
Membrane Proteins - genetics
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Mycobacterium tuberculosis
Mycobacterium tuberculosis - isolation & purification
Mycobacterium tuberculosis - physiology
Nitric oxide
Nitric Oxide Synthase - biosynthesis
Nitric Oxide Synthase - deficiency
Nitric Oxide Synthase - genetics
Polymerase Chain Reaction
Polymorphism, Genetic
Spleen
T lymphocytes
Tuberculosis
Tuberculosis - genetics
Tuberculosis - immunology
Tuberculosis - pathology
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Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.10.5243