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* Beatrice & Samuel A. Seaver Laboratory, Department of Medicine,
Cornell University Medical College, New York, NY 10021;
Communicated by Maclyn McCarty, The Rockefeller University, New
York, NY, March 13, 1997
(received for review December 9, 1996)
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
Proc. Natl. Acad. Sci. USA
Vol. 94,
pp. 5243-5248,
May 1997
Immunology
Identification of nitric oxide synthase as a protective locus
against tuberculosis
,,
, Trudeau
Institute, Saranac Lake, NY 12983; and Departments of
Immunology and Inflammation and § Medicinal Chemistry,
Merck Research Laboratories, Rahway, NJ 07065
/ 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.
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