title: Protection from hemolytic uremic syndrome by eyedrop vaccination with modified enterohemorrhagic E. coli outer membrane vesicles.
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.
authors.affiliation: The Graduate School of Yonsei University, Seoul, South Korea; Department of Ophthalmology, National Health Insurance Service Ilsan Hospital, Goyang city, South Korea.
authors.forename: Kyoung Sub
authors.initials: KS
authors.lastname: Choi
authors.affiliation: Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: The Graduate School of Yonsei University, Seoul, South Korea; Department of Ophthalmology, Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, South Korea.
authors.forename: Eun-Do
authors.initials: ED
authors.lastname: Kim
authors.affiliation: Viral Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Department of Ophthalmology, Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sangchul
authors.initials: S
authors.lastname: Yoon
authors.affiliation: The National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Chungbuk, South Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kyoung Yul
authors.initials: KY
authors.lastname: Seo
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004927:Escherichia coli Infections / Q000276:immunology; D019453:Escherichia coli O157 / Q000276:immunology / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000276:immunology / Q000627:therapeutic use*; D022361:Escherichia coli Vaccines / Q000276:immunology; D006463:Hemolytic-Uremic Syndrome / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D018928:Immunity, Mucosal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019081:O Antigens / Q000276:immunology; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000627:therapeutic use*; D014611:Vaccination / Q000379:methods*
chemical_list: D000907:Antibodies, Bacterial; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D019081:O Antigens; D009883:Ophthalmic Solutions; D003404:Creatinine