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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In common with all other living organisms, Gram-positive bacteria must continuously deal with stress situations in vivo. Such stress conditions may include changes in environmental temperature, pH, humidity, etc. In the case of many pathogens -including Mycobacterium tuberculosis, Staphylococcus aureus, Corynebacterium diphtherieae, Enterococcus phaecalis, Streptococcus pneumoniae or Bacillus anthracis -such changes include an efficient response to changing environments during both infection and virulence within the host. Other non-pathogenic and soil-dwelling bacteria, such as Streptomyces reticuli, Bacillus subtillis, Corynebacterium glutamicum or Mycobacterium snegmatis, must also respond to a wide variety of environmental stimuli including, UV-radiation or nutritional stress. All these bacteria have developed sensory systems that facilitate adaptation to changes in the environmental conditions. Recently, the three-component signalling system HbpS-SenS-SenR from the cellulose degrader Streptomyces reticuli has been reported as an example of a redox sensing pathway in bacteria. Using a combination of structural biology and in vivo and in vitro experiments it was demonstrated that the extracellular oligomer-forming protein HbpS acts in concert with the two-component system SenS-SenR in the sensing and reaction of the bacteria to heme-and iron-mediated oxidative stress. HbpS can bind and degrade heme via a non-enzymatic pathway known as coupled oxidation and it has been proposed that HbpS communicates the extracellular presence of heme and oxidative stress to the bacteria through the membrane-embedded sensor histidine kinase SenS using HbpS-bound iron ions. SenS subsequently phosphorylates the response regulator SenR, acting as a transcriptional regulator of a number of genes encoding for redox active proteins that are involved in the adaptation of the bacteria to oxidative stress. In this report, we analyze the sensing of signals by Gram-positive bacteria upon oxidative stress. We also focus further on the HbpS-SenS-SenR system and provide new insights into molecular mechanism used by Gram-positive bacteria to monitor and react to changes in environmental conditions. A knowledge of the interaction and reaction of bacteria to changes in their environment will open new avenues of understanding that could have many applications in fields as diverse as agriculture, biotechnology, ecosystem monitoring as well as human medicine.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis (TB) remains a major global health problem and although multiple studies have addressed the relationship between Mycobacterium tuberculosis (Mtb) and the host on an immunological level, few studies have addressed the impact of host physiological responses. Proteases produced by bacteria have been associated with important alterations in the host tissues and a limited number of these enzymes have been characterized in mycobacterial species. Mtb produces a protease called Zmp1, which appears to be associated with virulence, which has a putative action as an endothelin converting enzyme. Endothelins are a family of vasoactive peptides, of which 3 distinct isoforms exist and ET-1 is the most abundant and the best characterized isoform. The aim of this work was to characterize the Zmp1 protease and evaluate its role in pathogenicity. Here we have shown that M. tuberculosis produces and secretes an enzyme with ET-1 cleavage activity. These data demonstrate a possible role of Zmp1 for mycobacteria host interactions, and highlights its potential as a drug target. Moreover, the results suggest that endothelin pathways have a role in pathogenesis of Mtb infections, and ETA or ETB receptor signaling can modulate the host response to the infection. We hypothesize that a balance between Zmp1 control of ET-1 levels and ETA/ETB signaling can allow Mtb adaptation and survival in the lung tissues.
    Infection and immunity. 09/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis (Mtb) remains a major public health problem, with an effective vaccine continuing to prove elusive. Progress in vaccination strategies has been hampered by a lack of appreciation of the bacterium's response to dynamic changes in the host immune environment. Here, we utilize reporter Mtb strains that respond to specific host immune stresses such as hypoxia and nitric oxide (hspX'::GFP), and phagosomal maturation (rv2390c'::GFP), to investigate vaccine-induced alterations in the environmental niche during experimental murine infections. While vaccination undoubtedly decreased bacterial burden, we found that it also appeared to accelerate Mtb's adoption of a phenotype better equipped to survive in its host. We subsequently utilized a novel replication reporter strain of Mtb to demonstrate that, in addition to these alterations in host stress response, there is a decreased percentage of actively replicating Mtb in vaccinated hosts. This observation was supported by the differential sensitivity of recovered bacteria to the front-line drug isoniazid. Our study documents the natural history of the impact that vaccination has on Mtb's physiology and replication and highlights the value of reporter Mtb strains for probing heterogeneous Mtb populations in the context of a complex, whole animal model.
    PLoS Pathogens 09/2014; 10(9):e1004394. · 8.14 Impact Factor

Full-text (2 Sources)

Available from
Jun 4, 2014