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 Therapy
-
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