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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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 10; pp. 5243 - 5248
Main Authors:	MacMicking, John D., North, Robert J., LaCourse, Ron, Mudgett, John S., Shah, Shrenik K., Nathan, Carl F.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences of the United States of America 13-05-1997 National Acad Sciences National Academy of Sciences The National Academy of Sciences of the USA
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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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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom reprint requests should be addressed. e-mail: cnathan@med.cornell.edu. Maclyn McCarty, The Rockefeller University, New York, NY Present address: Laboratory of Immunology, The Rockefeller University, New York, NY 10021.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.94.10.5243