Identification of nitric oxide synthase as a protective locus against tuberculosis.

Beatrice & Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/1997; 94(10):5243-8. DOI: 10.1073/pnas.94.10.5243
Source: PubMed

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.

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    ABSTRACT: M.tb, which causes TB, is a host-adapted intracellular pathogen of macrophages. Macrophage intracellular PRRs, such as NOD proteins, regulate proinflammatory cytokine production in response to various pathogenic organisms. We demonstrated previously that NOD2 plays an important role in controlling the inflammatory response and viability of M.tb and Mycobacterium bovis BCG in human macrophages. Various inflammatory mediators, such as cytokines, ROS, and RNS, such as NO, can mediate this control. iNOS (or NOS2) is a key enzyme for NO production and M.tb control during infection of mouse macrophages; however, the role of NO during infection of human macrophages remains unclear, in part, as a result of the low amounts of NO produced in these cells. Here, we tested the hypothesis that activation of NOD2 by its ligands (MDP and GMDP, the latter from M.tb) plays an important role in the expression and activity of iNOS and NO production in human macrophages. We demonstrate that M.tb or M. bovis BCG infection enhances iNOS expression in human macrophages. The M.tb-induced iNOS expression and NO production are dependent on NOD2 expression during M.tb infection. Finally, NF-κB activation is required for NOD2-dependent expression of iNOS in human macrophages. Our data provide evidence for a new molecular pathway that links activation of NOD2, an important intracellular PRR, and iNOS expression and activity during M.tb infection of human macrophages. © Society for Leukocyte Biology.
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    ABSTRACT: Mycobacterium tuberculosis is an incredibly successful pathogen with an extraordinary penetrance of its target host population. The ability to infect many yet cause disease in few is undoubtedly central to this success. This ability relies on sensing and responding to the changing environments encountered during the course of disease in the human host. This chapter discusses these environmental cues and stresses, and explores how the genome of Mtb has evolved under the purifying selections that they exert. In analyzing the response of Mtb to a broad range of intracellular pressures it is clear that, despite genome down-sizing, Mtb has retained an extraordinary flexibility in central carbon metabolism. We believe that it is this metabolic plasticity, more than any of the virulence factors, that is the foundation for Mtb's qualities of endurance.

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