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PMID: 9144222 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 10 ·1997-05-13 ·Pages 5243-8

MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF

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.

MeSH Terms
Alleles Animals Carrier Proteins/biosynthesis,genetics Cation Transport Proteins Crosses, Genetic Disease Susceptibility Exons Female Genotype Glucocorticoids/pharmacology Haplotypes Heterozygote Homozygote Immunity, Innate/genetics Immunosuppression Therapy Isoenzymes/biosynthesis,deficiency,genetics Lung/microbiology,pathology Male Membrane Proteins/biosynthesis,genetics Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Mycobacterium tuberculosis/isolation & purification,physiology Nitric Oxide Synthase/biosynthesis,deficiency,genetics Polymerase Chain Reaction Polymorphism, Genetic Tuberculosis/genetics,immunology,pathology
Chemicals
Carrier Proteins Cation Transport Proteins Glucocorticoids Isoenzymes Membrane Proteins natural resistance-associated macrophage protein 1 Nitric Oxide Synthase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
MacMicking J D
Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021, USA.
North R J
LaCourse R
Mudgett J S
Shah S K
Nathan C F
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.94.10.5243
Published
1997-05-13
Pages
5243-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24663
Subset
IM
Grants
NIAID NIH HHS · AI34543 · United States
NHLBI NIH HHS · HL51960 · United States
NHLBI NIH HHS · HL51967 · United States
External Links
PubMed source DOI: 10.1073/pnas.94.10.5243 PMC Full Text View journal details
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