Identification of nitric oxide synthase as a protective locus against tuberculosis

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 N 6 -(1-iminoethyl)-Llysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…Thus, alternatively activated macrophages provide an iron-rich environment for intracellular M. tuberculosis. In mice, IFN-c-dependent downregulation of TfR contributed to inhibition of mycobacterial growth [48], as does NO production by iNOS [4]. Further studies will be required to elucidate to what extent observations in the murine model of tuberculosis can be extrapolated to the situation in humans, particularly as it has been demonstrated recently that IL-4 does not induce arginase in human monocytes and monocyte-derived macrophages [83,84].…”

“…In contrast, genes that formed part of the response of classically, but not alternatively, activated macrophages and that were not affected by IL-4 as compared to IFN-c activation in the uninfected stage included IL-1b, IL-1 family member 6 (IL-1F6), IL-12p40, CD44 and iNOS. Because NO production represents the critical defense mechanism in tuberculosis [4], we further investigated the influence of alternative macrophage activation on iNOS expression and NO production.…”

“…IFN-c-induced factors involved in protection against tuberculosis in vivo include inducible nitric oxide synthase (iNOS) [4], which generates reactive nitrogen intermediates, and the small GTPase LRG-47 [5]. As a result of T cell-mediated immunity, replication of M. tuberculosis is confined; however, a residual number of mycobacteria may enter a dormant stage such that latently infected individuals stand a 10% risk of disease reactivation later in life.…”

Mycobacterium bovis Bacillus Calmette-Guérin Vaccination Mobilizes Innate Myeloid-Derived Suppressor Cells Restraining In Vivo T Cell Priming via IL-1R–Dependent Nitric Oxide Production

“…Whereas MDSCs accumulate in lymphoid tissues, inMDSCs appeared early after BCG injection, first in the blood and skin, where they peaked by day 3. In mice, iNOS and NO production induced by classically activated macrophages is essential for the destruction of mycobacteria (36). However, pathogenic mycobacteria escape this harsh environment by FIGURE 5.…”

Efficient tuberculosis treatment in mice using chemotherapy and immunotherapy with the combined DNA vaccine encoding Ag85B, MPT-64 and MPT-83

“…NO is an important mediator in the control of M. tuberculosis infection. 28 Higher NO levels detected in splenocytes of mice treated with combined DNA vaccine and antibiotics may therefore enhance resistance of mouse to M. tuberculosis infection. In summary, the present study demonstrates that vaccination with Ag85B, MPT-64 and MPT-83 DNA during chemotherapy conferred a protective effect against M. tuberculosis reactivation.…”