Identification of NOS2 as a protective locus against tuberculosis

Department of Medicine, Cornell University, Итак, New York, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/1997; 94(10):5243-8. DOI: 10.1073/pnas.94.10.5243
Source: PubMed


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.

Download full-text


Available from: John S Mudgett, Dec 18, 2013
  • Source
    • "In particular, mice deficient in CD4 + subset and Th1 type cytokines (i.e., IL-12p40, IFN-í µí»¾) succumb early to Mtb infection with high bacterial loads [21] [22] [23]. Similar effects are observed in mice with the defects in enzymes involved in the generation of host-bactericidal molecules, dependent on IFN-í µí»¾ axis [24] [25] [26] [27]. Humans with the mutations in molecules involved in Th1 immunity (i.e., the IL-12p40 subunit, the IL-12 receptor í µí»½1 chain, the IFN-í µí»¾-receptor ligand binding chain, and STAT1) exhibit extremely high susceptibility to infections induced by Mtb, Bacillus Calmette-Guerin (BCG), or environmental mycobacteria [28–30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen “activity,” host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4+ T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4+ T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.
    Full-text · Article · Nov 2015 · Mediators of Inflammation
  • Source
    • "Further study found that EHEC possessing functional norV exhibited increased survival within macrophages compared to strains harboring the inactive norVs gene (Shimizu et al., 2012). Furthermore, murine infection studies have shown that deletion or inhibition of inducible nitric oxide synthase (iNOS), the enzyme responsible for NO • production in phagocytes (MacMicking et al., 1997), increases the bacterial load and mortality rate of infected hosts for a wide variety of pathogens (Richardson et al., 2011; MacMicking et al., 1995; Chan et al., 1995; Bang et al., 2006). These data suggest that sabotaging bacterial NO • defenses could constitute an effective anti-infective strategy for many pathogens. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of NO• to immunity is highlighted by the diversity of pathogens that require NO•-defensive systems to establish infections. Proteases have been identified to aid pathogens in surviving macrophage attack, inspiring us to investigate their role during NO• stress in Escherichia coli. We discovered that the elimination of ClpP largely impaired NO• detoxification by E. coli. Using a quantitative model of NO• stress, we employed an ensemble-guided approach to identify the underlying mechanism. Iterations of in silico analyses and corresponding experiments identified the defect to result from deficient transcript levels of hmp, which encodes NO• dioxygenase. Interestingly, the defect was not confined to hmp, as ΔclpP imparted widespread perturbations to the expression of NO•-responsive genes. This work identified a target for anti-infective therapies based on disabling NO• defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO•. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Metabolic Engineering
  • Source
    • "However, given the multifaceted role of nitric oxide in both the cytotoxicity and cytoprotection of pathogens, inhibiting nitric oxide production may also yield deleterious effects. For example, administration of the iNOS-2 inhibitor N 6 -(1-iminoethyl)-L-lysine caused accelerated progression of M. tuberculosis infection to chronic tuberculosis in murine lungs (MacMicking et al., 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The emergence and spread of drug-resistant pathogens and our inability to develop new antimicrobials to overcome resistance has inspired scientists to consider new targets for drug development. Cellular bioenergetics is an area showing promise for the development of new antimicrobials, particularly in the discovery of new anti-tuberculosis drugs where several new compounds have entered clinical trials. In this review, we have examined the bioenergetics of various bacterial pathogens, highlighting the versatility of electron donor and acceptor utilisation and the modularity of electron transport chain components in bacteria. In addition to re-examining classical concepts, we explore new literature that reveals the intricacies of pathogen energetics, for example, how Salmonella enterica and Campylobacter jejuni exploit host and microbiota to derive powerful electron donors and sinks; the strategies Mycobacterium tuberculosis and Pseudomonas aeruginosa use to persist in lung tissues; and the importance of sodium energetics and electron bifurcation in the chemiosmotic anaerobe Fusobacterium nucleatum. A combination of physiological, biochemical, and pharmacological data suggests that, in addition to the clinically-approved target F1Fo-ATP synthase, NADH dehydrogenase type II, succinate dehydrogenase, hydrogenase, cytochrome bd oxidase, and menaquinone biosynthesis pathways are particularly promising next-generation drug targets. The realisation of cellular energetics as a rich target space for the development of new antimicrobials will be dependent upon gaining increased understanding of the energetic processes utilised by pathogens in host environments and the ability to design bacterial-specific inhibitors of these processes.
    Full-text · Article · Nov 2014 · Advances in Microbial Physiology
Show more