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      Protection from Hemolytic Uremic Syndrome by Eyedrop Vaccination with Modified Enterohemorrhagic E. coli Outer Membrane Vesicles

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          Abstract

          We investigated whether eyedrop vaccination using modified outer membrane vesicles (mOMVs) is effective for protecting against hemolytic uremic syndrome (HUS) caused by enterohemorrhagic E. coli (EHEC) O157:H7 infection. Modified OMVs and waaJ-mOMVs were prepared from cultures of MsbB- and Shiga toxin A subunit (STxA)-deficient EHEC O157:H7 bacteria with or without an additional waaJ mutation. BALB/c mice were immunized by eyedrop mOMVs, waaJ-mOMVs, and mOMVs plus polymyxin B (PMB). Mice were boosted at 2 weeks, and challenged peritoneally with wild-type OMVs (wtOMVs) at 4 weeks. As parameters for evaluation of the OMV-mediated immune protection, serum and mucosal immunoglobulins, body weight change and blood urea nitrogen (BUN)/Creatinin (Cr) were tested, as well as histopathology of renal tissue. In order to confirm the safety of mOMVs for eyedrop use, body weight and ocular histopathological changes were monitored in mice. Modified OMVs having penta-acylated lipid A moiety did not contain STxA subunit proteins but retained non-toxic Shiga toxin B (STxB) subunit. Removal of the polymeric O-antigen of O157 LPS was confirmed in waaJ-mOMVs. The mice group vaccinated with mOMVs elicited greater humoral and mucosal immune responses than did the waaJ-mOMVs and PBS-treated groups. Eyedrop vaccination of mOMVs plus PMB reduced the level of humoral and mucosal immune responses, suggesting that intact O157 LPS antigen can be a critical component for enhancing the immunogenicity of the mOMVs. After challenge, mice vaccinated with mOMVs were protected from a lethal dose of wtOMVs administered intraperitoneally, conversely mice in the PBS control group were not. Collectively, for the first time, EHEC O157-derived mOMV eyedrop vaccine was experimentally evaluated as an efficient and safe means of vaccine development against EHEC O157:H7 infection-associated HUS.

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          Most cited references 36

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          Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.

          Most cases of diarrhoea-associated haemolytic uraemic syndrome (HUS) are caused by Shiga-toxin-producing bacteria; the pathophysiology differs from that of thrombotic thrombocytopenic purpura. Among Shiga-toxin-producing Escherichia coli (STEC), O157:H7 has the strongest association worldwide with HUS. Many different vehicles, in addition to the commonly suspected ground (minced) beef, can transmit this pathogen to people. Antibiotics, antimotility agents, narcotics, and non-steroidal anti-inflammatory drugs should not be given to acutely infected patients, and we advise hospital admission and administration of intravenous fluids. Management of HUS remains supportive; there are no specific therapies to ameliorate the course. The vascular injury leading to HUS is likely to be well under way by the time infected patients seek medical attention for diarrhoea. The best way to prevent HUS is to prevent primary infection with Shiga-toxin-producing bacteria.
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            Bacterial outer membrane vesicles and the host-pathogen interaction.

             N C Kesty,  Meta Kuehn (2005)
            Extracellular secretion of products is the major mechanism by which Gram-negative pathogens communicate with and intoxicate host cells. Vesicles released from the envelope of growing bacteria serve as secretory vehicles for proteins and lipids of Gram-negative bacteria. Vesicle production occurs in infected tissues and is influenced by environmental factors. Vesicles play roles in establishing a colonization niche, carrying and transmitting virulence factors into host cells, and modulating host defense and response. Vesicle-mediated toxin delivery is a potent virulence mechanism exhibited by diverse Gram-negative pathogens. The biochemical and functional properties of pathogen-derived vesicles reveal their potential to critically impact disease.
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              Characterisation of the Escherichia coli strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study.

              In an ongoing outbreak of haemolytic uraemic syndrome and bloody diarrhoea caused by a virulent Escherichia coli strain O104:H4 in Germany (with some cases elsewhere in Europe and North America), 810 cases of the syndrome and 39 deaths have occurred since the beginning of May, 2011. We analysed virulence profiles and relevant phenotypes of outbreak isolates recovered in our laboratory. We analysed stool samples from 80 patients that had been submitted to the National Consulting Laboratory for Haemolytic Uraemic Syndrome in Münster, Germany, between May 23 and June 2, 2011. Isolates were screened with standard PCR for virulence genes of Shiga-toxin-producing E coli and a newly developed multiplex PCR for characteristic features of the outbreak strain (rfb(O104), fliC(H4), stx(2), and terD). Virulence profiles of the isolates were determined with PCR targeting typical virulence genes of Shiga-toxin-producing E coli and of other intestinal pathogenic E coli. We sequenced stx with Sanger sequencing and measured Shiga-toxin production, adherence to epithelial cells, and determined phylogeny and antimicrobial susceptibility. All isolates were of the HUSEC041 clone (sequence type 678). All shared virulence profiles combining typical Shiga-toxin-producing E coli (stx(2), iha, lpf(O26), lpf(O113)) and enteroaggregative E coli (aggA, aggR, set1, pic, aap) loci and expressed phenotypes that define Shiga-toxin-producing E coli and enteroaggregative E coli, including production of Shiga toxing 2 and aggregative adherence to epithelial cells. Isolates additionally displayed an extended-spectrum β-lactamase phenotype absent in HUSEC041. Augmented adherence of the strain to intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome. This outbreak demonstrates that blended virulence profiles in enteric pathogens, introduced into susceptible populations, can have extreme consequences for infected people. German Federal Ministry of Education and Research, Network Zoonoses. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Affiliations
                [1 ]The Graduate School of Yonsei University, Seoul, South Korea
                [2 ]Department of Ophthalmology, National Health Insurance Service Ilsan Hospital, Goyang city, South Korea
                [3 ]Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
                [4 ]Department of Ophthalmology, Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea
                [5 ]Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, South Korea
                [6 ]The National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Chungbuk, South Korea
                Indian Institute of Science, India
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KSC EDK SHK KTC KYS. Performed the experiments: KSC EDK SHL SJH SCY. Analyzed the data: KSC EDK SJH SCY KYS. Contributed reagents/materials/analysis tools: SHK SHL. Wrote the paper: KSC SHK EDK. Helped write and revise the manuscript: EDK KYS.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                17 July 2014
                : 9
                : 7
                PONE-D-13-44608
                10.1371/journal.pone.0100229
                4102476
                25032703

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Pages: 8
                Funding
                This study was supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (Grant No.: A121861). Additional funding was received from the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2013M3A9D5072551). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Molecular Cell Biology
                Immunology
                Vaccination and Immunization
                Vaccine Development
                Vaccines
                Clinical Immunology
                Immune Response
                Immunity
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Escherichia Coli
                Medicine and Health Sciences

                Uncategorized

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