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      Nitric oxide blocks the development of the human parasiteSchistosoma japonicum

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          Abstract

          <p id="d15060116e372">Viable egg production by <i>Schistosoma</i> species is the key pathogenic process causing granuloma formation in permissive hosts (e.g., mice), while nonpermissive hosts [e.g., Norway rats ( <i>Rattus norvegicus</i>)] avoid such sequelae. Using inducible nitric oxide synthase knockout (iNOS <sup>−/−</sup>) rats, we demonstrate that high expression levels of iNOS in rats play an important role in blocking the egg-induced granuloma formation of <i>Schistosoma japonicum</i>. The nitric oxide, produced by iNOS, inhibits parasite growth, reproductive organ development, egg production, and viability by interfering with mitochondrial function. This study solves the puzzle as to why rats are naturally resistant to <i>S. japonicum</i> infection and provides insights for understanding the pathogenesis of human schistosomiasis and the interactions between host and parasite. </p><p class="first" id="d15060116e390">Human schistosomiasis, caused by <i>Schistosoma</i> species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats ( <i>Rattus norvegicus</i>), are naturally intolerant to <i>Schistosoma japonicum</i> infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS <sup>−/−</sup>) Sprague–Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in <i>S. japonicum</i>, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS <sup>−/−</sup> rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in <i>S. japonicum</i> but also offers insights into a better understanding of host–parasite interactions and drug development strategies against schistosomiasis. </p>

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          Most cited references45

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          Nitric oxide and macrophage function.

          At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
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            The Schistosoma japonicum genome reveals features of host-parasite interplay.

            (2009)
            Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis, which is a significant cause of morbidity in China and the Philippines. Here we present a draft genomic sequence for the worm. The genome provides a global insight into the molecular architecture and host interaction of this complex metazoan pathogen, revealing that it can exploit host nutrients, neuroendocrine hormones and signalling pathways for growth, development and maturation. Having a complex nervous system and a well-developed sensory system, S. japonicum can accept stimulation of the corresponding ligands as a physiological response to different environments, such as fresh water or the tissues of its intermediate and mammalian hosts. Numerous proteases, including cercarial elastase, are implicated in mammalian skin penetration and haemoglobin degradation. The genomic information will serve as a valuable platform to facilitate development of new interventions for schistosomiasis control.
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              The chemical biology of nitric oxide: implications in cellular signaling.

              Nitric oxide (NO) has earned the reputation of being a signaling mediator with many diverse and often opposing biological activities. The diversity in response to this simple diatomic molecule comes from the enormous variety of chemical reactions and biological properties associated with it. In the past few years, the importance of steady-state NO concentrations has emerged as a key determinant of its biological function. Precise cellular responses are differentially regulated by specific NO concentration. We propose five basic distinct concentration levels of NO activity: cGMP-mediated processes ([NO] 400 nM), and nitrosative stress (1 microM). In general, lower NO concentrations promote cell survival and proliferation, whereas higher levels favor cell cycle arrest, apoptosis, and senescence. Free radical interactions will also influence NO signaling. One of the consequences of reactive oxygen species generation is to reduce NO concentrations. This antagonizes the signaling of nitric oxide and in some cases results in converting a cell-cycle arrest profile to a cell survival profile. The resulting reactive nitrogen species that are generated from these reactions can also have biological effects and increase oxidative and nitrosative stress responses. A number of factors determine the formation of NO and its concentration, such as diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. These are the chemical and biochemical parameters that shape cellular responses to NO. Herein we discuss signal transduction and the chemical biology of NO in terms of the direct and indirect reactions.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                September 19 2017
                September 19 2017
                September 19 2017
                September 05 2017
                : 114
                : 38
                : 10214-10219
                Article
                10.1073/pnas.1708578114
                5617295
                28874579
                5e913d82-f634-4da4-8d4b-f53961492cc7
                © 2017

                Free to read

                http://www.pnas.org/site/misc/userlicense.xhtml

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