Mice lacking inducible nitric-oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses

Division of Virology, University of Glasgow, UK.
Journal of General Virology (Impact Factor: 3.18). 05/1998; 79 ( Pt 4)(4):825-30. DOI: 10.1099/0022-1317-79-4-825
Source: PubMed


Mice deficient in the inducible nitric-oxide synthase (iNOS), constructed by gene-targeting, were significantly more susceptible to herpes simplex virus (HSV)-1 infection, displayed a delayed clearance of virus from the dorsal root ganglia (DRG) and exhibited an increase in the frequency of virus reactivation in DRG compared with similarly infected heterozygous mice. The infected iNOS-deficient mice developed enhanced Th1-type immune responses and their spleen cells produced higher concentrations of IL-12 than similarly infected heterozygous mice. This finding suggests that iNOS plays an important role in resistance against HSV-1 infection. Furthermore, nitric oxide (NO) may block the development of Th1 cells via inhibition of IL-12 synthesis and thereby play a role in immune regulation.

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    • "We have found in this study the importance of iNOS as the enzyme by which nitric oxide is synthesized. This is not surprising, as iNOS induction in response to virus infection, as well as viral components, is well known [56]–[58]. During viral infection, nitric oxide production by iNOS is induced by cytokines such as IFN-γ; however, virus infection can up-regulate iNOS independently of such cytokines [29]. "
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    ABSTRACT: The innate host response to virus infection is largely dominated by the production of type I interferon and interferon stimulated genes. In particular, fibroblasts respond robustly to viral infection and to recognition of viral signatures such as dsRNA with the rapid production of type I interferon; subsequently, fibroblasts are a key cell type in antiviral protection. We recently found, however, that primary fibroblasts deficient for the production of interferon, interferon stimulated genes, and other cytokines and chemokines mount a robust antiviral response against both DNA and RNA viruses following stimulation with dsRNA. Nitric oxide is a chemical compound with pleiotropic functions; its production by phagocytes in response to interferon-γ is associated with antimicrobial activity. Here we show that in response to dsRNA, nitric oxide is rapidly produced in primary fibroblasts. In the presence of an intact interferon system, nitric oxide plays a minor but significant role in antiviral protection. However, in the absence of an interferon system, nitric oxide is critical for the protection against DNA viruses. In primary fibroblasts, NF-κB and interferon regulatory factor 1 participate in the induction of inducible nitric oxide synthase expression, which subsequently produces nitric oxide. As large DNA viruses encode multiple and diverse immune modulators to disable the interferon system, it appears that the nitric oxide pathway serves as a secondary strategy to protect the host against viral infection in key cell types, such as fibroblasts, that largely rely on the type I interferon system for antiviral protection.
    PLoS ONE 02/2012; 7(2):e31688. DOI:10.1371/journal.pone.0031688 · 3.23 Impact Factor
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    • "Production of NO by one of the inducible isoenzyme of the nitric oxide synthase enzyme family (iNOS) has been directly correlated to the host's ability to suppress microbial proliferation and contain the infection [16]. Mice lacking the iNOS are more susceptible to infection as compared to their wild-type counterpart [17]. In vitro studies utilizing a number of different NO donors suggest that NO possesses antimicrobial activity against a wide range of phyla including bacteria, viruses, helminthes , and parasites [18] [19]. "
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    ABSTRACT: Exogenous gaseous nitric oxide (gNO) is an FDA approved drug for treatment of a variety of human pathologies like Persistent Pulmonary Hypertension in neonates and premature babies, skin lesions and fungal dermatophyte infections. Substantial disadvantages of current gNO-based therapies are the high therapy costs, high storage costs of the gas cylinders, and the rapid contamination of compressed NO gases with various decomposition products. Here we describe a new, very simple, and inexpensive photolytic generator of uncontaminated NO-containing gas mixtures at therapeutic concentrations. The new method bases on UVA-induced and redox-assisted decomposition of nitrite ions in aqueous solutions. NO formation via UVA-induced photolysis of nitrite is accompanied by an OH radical-dependent production of NO(2) that beside its toxic character additionally strongly reduces the NO yield by consuming NO in its reaction to N(2)O(3). During the UVA-induced photodecomposition process both, inhibition of NO(2) formation or NO(2) depletion by antioxidants hinders the NO-consuming reaction with NO(2) and ensured a maximal purity and maximal yield of NO-containing gas mixtures. Therefore, NO-containing gas mixtures generated by the described method are suitable for medical applications like inhalation or gassing of chronic non-healing wounds. Control of temperature, UVA intensity and composition of the reaction mixture allows facile control over the final NO level in the carrier gas over a wide concentration range. We demonstrate the sustained and stable release of NO over a wide dynamic range (10-5000 ppm NO) for many hours. The method avoids contamination-prone long time storage of NO gas. As such, it appears particularly relevant for applications involving the additional presence of oxygen (e.g. inhalation).
    Nitric Oxide 12/2010; 23(4):275-83. DOI:10.1016/j.niox.2010.08.001 · 3.52 Impact Factor
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    • "Production of NO has been directly correlated to the host's ability to suppress microbial proliferation (MacMicking et al., 1997b). Mice lacking the inducible form of iNOS are more susceptible to infection compared with their wild-type counterpart (MacLean et al., 1998). In vitro studies utilizing a number of different NO donors suggest that NO possesses antimicrobial activity against bacteria, viruses, helminths and parasites (Sager et al., 1997; Saura et al., 1999; Weller et al., 2001). "
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    ABSTRACT: NO (nitric oxide) molecule is produced by various mammalian cell types and plays a significant role in inflammation, infection and wound healing processes. Recently, gNO (gaseous nitric oxide) therapy has been utilized for its potential clinical application as an antimicrobial agent, with special focus on skin infection. In a previous study, we demonstrated that 200 ppm gNO, 8 h/day for three consecutive days significantly reduced the number of bacteria in dermal wounds without compromising the viability and function of skin cells. To increase the feasibility and ease of its clinical use, we propose that different doses of gNO (5 to 10 K ppm) for 8 h and as short as 10 min be used, respectively. To achieve this, we set up in vitro experiments and asked whether (i) different doses of gNO have any toxic effect on immune cells and (ii) gNO has any modulating effect on key ECM (extracellular matrix) components in fibroblasts. To further investigate the effect of gNO, expression of more than 100 key ECM genes have been examined using gene array in human fibroblasts. As immune cells play an important role in wound healing, the effect of gNO on proliferation and viability of human and mouse lymphocytes was also examined. The findings showed that, the 5, 25, 75 and 200 ppm of gNO for 8 h slightly increased the expression of Col 5A3 (collagen type V alpha 3), and gNO at 5 ppm decreased the expression of MMP-1 (matrix metalloproteinase 1), while exposure of fibroblast to 10 K ppm of gNO for 10 min does not show any significant changes in ECM genes. Exposure to gNO resulted in inhibition of lymphocyte proliferation without affecting the cell viability. Taken together, our findings show that skin could be treated with gNO without compromising the role of ECM and immune cells in low concentrations with long time exposure or high concentrations for a shorter exposure time.
    Cell Biology International 12/2010; 35(4):407-15. DOI:10.1042/CBI20100420 · 1.93 Impact Factor
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