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      Type VI secretion system-associated FHA domain protein TagH regulates the hemolytic activity and virulence of Vibrio cholerae

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          ABSTRACT

          The type VI secretion system (T6SS) and hemolysin HlyA are important virulence factors in Vibrio cholerae. The forkhead-associated (FHA) domain is a conserved phosphopeptide binding domain that exists in many regulatory modules. The FHA domain protein-encoding gene is conserved in the T6SS gene cluster and regulates the assembly and secretion of the T6SS. This study shows for the first time that the FHA domain protein TagH plays a role in controlling the hemolytic activity of V. cholerae, in addition to regulating the T6SS. TagH negatively regulates HlyA expression at the transcriptional and post-translational levels. The phosphopeptide binding sites of the FHA domain of TagH play a key role in the regulation of hemolytic activity. The deletion of tagH enhances the intestinal pathogenicity and extraintestinal invasion ability of V. cholerae, which mainly depend on the expression of HlyA. This study provides evidence that helps unravel the novel regulatory role of TagH in HlyA and provides critical insights which will aid in the development of strategies to manage HlyA.

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          Most cited references71

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          Cholera.

          Despite more than a century of study, cholera still presents challenges and surprises to us. Throughout most of the 20th century, cholera was caused by Vibrio cholerae of the O1 serogroup and the disease was largely confined to Asia and Africa. However, the last decade of the 20th century has witnessed two major developments in the history of this disease. In 1991, a massive outbreak of cholera started in South America, the one continent previously untouched by cholera in this century. In 1992, an apparently new pandemic caused by a previously unknown serogroup of V. cholerae (O139) began in India and Bangladesh. The O139 epidemic has been occurring in populations assumed to be largely immune to V. cholerae O1 and has rapidly spread to many countries including the United States. In this review, we discuss all aspects of cholera, including the clinical microbiology, epidemiology, pathogenesis, and clinical features of the disease. Special attention will be paid to the extraordinary advances that have been made in recent years in unravelling the molecular pathogenesis of this infection and in the development of new generations of vaccines to prevent it.
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            Cholera

            Cholera is an acute, watery diarrhoeal disease caused by Vibrio cholerae of the O1 or O139 serogroups. In the past two centuries, cholera has emerged and spread from the Ganges Delta six times and from Indonesia once to cause global pandemics. Rational approaches to the case management of cholera with oral and intravenous rehydration therapy have reduced the case fatality of cholera from more than 50% to much less than 1%. Despite improvements in water quality, sanitation, and hygiene, as well as in the clinical treatment of cholera, the disease is still estimated to cause about 100 000 deaths every year. Most deaths occur in cholera-endemic settings, and virtually all deaths occur in developing countries. Contemporary understanding of immune protection against cholera, which results from local intestinal immunity, has yielded safe and protective orally administered cholera vaccines that are now globally stockpiled for use in the control of both epidemic and endemic cholera.
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              Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system.

              The bacterium Vibrio cholerae, like other human pathogens that reside in environmental reservoirs, survives predation by unicellular eukaryotes. Strains of the O1 and O139 serogroups cause cholera, whereas non-O1/non-O139 strains cause human infections through poorly defined mechanisms. Using Dictyostelium discoideum as a model host, we have identified a virulence mechanism in a non-O1/non-O139 V. cholerae strain that involves extracellular translocation of proteins that lack N-terminal hydrophobic leader sequences. Accordingly, we have named these genes "VAS" genes for virulence-associated secretion, and we propose that these genes encode a prototypic "type VI" secretion system. We show that vas genes are required for cytotoxicity of V. cholerae cells toward Dictyostelium amoebae and mammalian J774 macrophages by a contact-dependent mechanism. A large number of Gram-negative bacterial pathogens carry genes homologous to vas genes and potential effector proteins secreted by this pathway (i.e., hemolysin-coregulated protein and VgrG). Mutations in vas homologs in other bacterial species have been reported to attenuate virulence in animals and cultured macrophages. Thus, the genes encoding the VAS-related, type VI secretion system likely play an important conserved function in microbial pathogenesis and represent an additional class of targets for vaccine and antimicrobial drug-based therapies.

                Author and article information

                Journal
                Gut Microbes
                Gut Microbes
                Gut Microbes
                Taylor & Francis
                1949-0976
                1949-0984
                6 April 2022
                2022
                6 April 2022
                : 14
                : 1
                : 2055440
                Affiliations
                [a ]Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University; , Zunyi, Guizhou, China
                [b ]School of Laboratory Medicine, Zunyi Medical University; , Zunyi, Guizhou, China
                Author notes
                CONTACT Xun Min minxunzmu@ 123456163.com Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University; , Zunyi, Guizhou, China
                Jian Huang 81537648@ 123456qq.com School of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University; , Zunyi,Guizhou, China

                *These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-7118-2177
                Article
                2055440
                10.1080/19490976.2022.2055440
                8993066
                35383540
                f5427d27-80db-4ac3-90d2-121a7f66aab8
                © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 9, References: 71, Pages: 1
                Categories
                Research Article
                Research Paper

                Microbiology & Virology
                vibrio cholerae,forkhead-associated domain,tagh,type vi secretion system,hemolysin

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