Identification of nitric oxide synthase as a protective locus against tuberculosis

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 primaryMycobacterium tuberculosisinfection using mice homozygous for a disruptedNOS2allele. NOS2^−/−mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowedMycobacterium tuberculosisto 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 ofN⁶-(1-iminoethyl)-