Identification of nitric oxide synthase as a protective locus against tuberculosis

MacMicking, John D.; North, Robert J.; LaCourse, Ron; Mudgett, John S.; Shah, Shrenik K.; Nathan, Carl F.

doi:10.1073/pnas.94.10.5243

Cited by 1,180Tuberculosis Research and EpidemiologyImmune responses and vaccinationsImmune Response and Inflammation

Identification of nitric oxide synthase as a protective locus against tuberculosis

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MacMicking, John D., North, Robert J., LaCourse, Ron, Mudgett, John S., Shah, Shrenik K., Nathan, Carl F.·1997·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.94.10.5243PMC PMC24663

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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 N 6 -(1-iminoethyl)- l -lysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.

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Highly reactive intermediates execute their microbicidal activity by oxidative destruction of membrane lipids, DNA, thiol and tyrosine residues, whereas NO can exert toxicity by directly targeting iron sulfur clusters of central metabolic enzymes.
“Nonetheless, these highly reactive intermediates execute their microbicidal activity by oxidative destruction of membrane lipids, DNA, thiol and tyrosine residues, whereas NO can exert toxicity by directly targeting iron sulfur cluster of central metabolic enzymes (57, 58, 70–72).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [72]

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Authors: MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., Shah, S. K., & Nathan, C. F.
Affiliations: Trudeau Institute (US)
Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021; Trudeau Institute, Saranac Lake, NY 12983; and Departments of Immunology and Inflammation and Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065
Corresponding author: MacMicking, John D.
Nathan, Carl F.
ORCID: MacMicking, John D.
Nathan, Carl F.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1997-05-13
Volume: 94
Issue: 10
Pages: 5243-5248
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.94.10.5243
PMC: PMC24663
OpenAlex: W2019255399
Cited by: 1,180
References: 49
Citations by year: 2026: 28 · 2025: 16 · 2024: 23 · 2023: 22 · 2022: 23 · 2021: 41 · 2020: 33 · 2019: 42 · 2018: 43 · 2017: 39 · 2016: 46 · 2015: 46 · 2014: 50 · 2013: 43 · 2012: 44
FWCI: 39.49
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1r01hl051960-01, 5r01hl051967-08)
National Heart, Lung, and Blood Institute (HL51967, HL-51960)
National Institute of Allergy and Infectious Diseases (AI-34543)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: inducible nitric oxide synthase, NOS2, tuberculosis, Mycobacterium tuberculosis, host resistance, NOS2 knockout mice, glucocorticoid-induced immunosuppression, NRAMP1, chronic tuberculosis, nitric oxide inhibition, host immune response
MeSH terms: Natural Resistance-associated Macrophage Protein 1, Alleles, Animals, Carrier Proteins, Crosses, Genetic, Disease Susceptibility, Exons, Female, Genotype, Glucocorticoids, Haplotypes, Heterozygote, Homozygote, Immunity, Innate, Immunosuppression Therapy, Isoenzymes, Lung, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Inbred Strains, Mycobacterium tuberculosis, Polymorphism, Genetic, Tuberculosis, Polymerase Chain Reaction, Mice, Knockout, Nitric Oxide Synthase, Cation Transport Proteins, Mice

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Identification of nitric oxide synthase as a protective locus against tuberculosis

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