Identification of nitric oxide synthase as a protective locus against tuberculosis

Proc Natl Acad Sci U S A. 1997 May 13;94(10):5243-8. doi: 10.1073/pnas.94.10.5243.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Cation Transport Proteins*
  • Crosses, Genetic
  • Disease Susceptibility
  • Exons
  • Female
  • Genotype
  • Glucocorticoids / pharmacology
  • Haplotypes
  • Heterozygote
  • Homozygote
  • Immunity, Innate / genetics*
  • Immunosuppression
  • Isoenzymes / biosynthesis
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Lung / microbiology
  • Lung / pathology
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mycobacterium tuberculosis / isolation & purification
  • Mycobacterium tuberculosis / physiology*
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / deficiency*
  • Nitric Oxide Synthase / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Tuberculosis / genetics*
  • Tuberculosis / immunology*
  • Tuberculosis / pathology

Substances

  • Carrier Proteins
  • Cation Transport Proteins
  • Glucocorticoids
  • Isoenzymes
  • Membrane Proteins
  • natural resistance-associated macrophage protein 1
  • Nitric Oxide Synthase