title: Mutation of the Enterohemorrhagic Escherichia coli Core LPS Biosynthesis Enzyme RfaD Confers Hypersusceptibility to Host Intestinal Innate Immunity In vivo.
abstract: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important foodborne pathogen causing severe diseases in humans worldwide. Currently, there is no specific treatment available for EHEC infection and the use of conventional antibiotics is contraindicated. Therefore, identification of potential therapeutic targets and development of effective measures to control and treat EHEC infection are needed. Lipopolysaccharides (LPS) are surface glycolipids found on the outer membrane of gram-negative bacteria, including EHEC, and LPS biosynthesis has long been considered as potential anti-bacterial target. Here, we demonstrated that the EHEC rfaD gene that functions in the biosynthesis of the LPS inner core is required for the intestinal colonization and pathogenesis of EHEC in vivo. Disruption of the EHEC rfaD confers attenuated toxicity in Caenorhabditis elegans and less bacterial colonization in the intestine of C. elegans and mouse. Moreover, rfaD is also involved in the control of susceptibility of EHEC to antimicrobial peptides and host intestinal immunity. It is worth noting that rfaD mutation did not interfere with the growth kinetics when compared to the wild-type EHEC cells. Taken together, we demonstrated that mutations of the EHEC rfaD confer hypersusceptibility to host intestinal innate immunity in vivo, and suggested that targeting the RfaD or the core LPS synthesis pathway may provide alternative therapeutic regimens for EHEC infection.
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
authors: Cheng-Ju
authors: CJ
authors: Kuo
authors: Center of Infectious Disease and Signaling Research, National Cheng Kung University Tainan, Taiwan.
authors: Jenn-Wei
authors: JW
authors: Chen
authors: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Taipei, Taiwan.
authors: Hao-Chieh
authors: HC
authors: Chiu
authors: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors: Ching-Hao
authors: CH
authors: Teng
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
authors: Tai-I
authors: TI
authors: Hsu
authors: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors: Pei-Jung
authors: PJ
authors: Lu
authors: Institute of Microbiology and Immunology, National Yang Ming University Taipei, Taiwan.
authors: Wan-Jr
authors: WJ
authors: Syu
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors: Sin-Tian
authors: ST
authors: Wang
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors: Ting-Chen
authors: TC
authors: Chou
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
authors: Chang-Shi
authors: CS
authors: Chen
mesh_terms: D000199:Actins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000276:immunology / Q000378:metabolism; D002238:Carbohydrate Epimerases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000628:therapy; D019453:Escherichia coli O157 / Q000201:enzymology* / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007410:Intestinal Diseases / Q000276:immunology / Q000382:microbiology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000096:biosynthesis* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D017384:Sequence Deletion; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
chemical_list: C505596:ACT-5 protein, C elegans; D000199:Actins; D023181:Antimicrobial Cationic Peptides; D029742:Caenorhabditis elegans Proteins; D029968:Escherichia coli Proteins; D008070:Lipopolysaccharides; D037521:Virulence Factors; C037213:ADP-L-glycero-D-mannoheptose-6-epimerase; D002238:Carbohydrate Epimerases; C580834:hldD protein, E coli; D054804:Cathelicidins
keywords: Caenorhabditis elegans; RfaD/GmhD/WaaD; antimicrobial peptides (AMPs); enterohemorrhagic Escherichia coli (EHEC); intestinal innate immunity; lipopolysaccharide (LPS)