title: Blood Group O-Dependent Cellular Responses to Cholera Toxin: Parallel Clinical and Epidemiological Links to Severe Cholera.
abstract: Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals. Likewise, using CRISPR/Cas9 engineering, a functional group O line (HT-29-A(-/-)) was generated from a parent group A HT-29 line. CT stimulated robust cAMP responses in HT-29-A(-/-) cells relative to HT-29 cells. These findings provide a direct molecular link between blood group O expression and differential cellular responses to CT, recapitulating clinical and epidemiologic observations.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: F Matthew
authors.initials: FM
authors.lastname: Kuhlmann
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Santhanam
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri. Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Ciorba
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri. Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri. Veterans Affairs Medical Center, Saint Louis, Missouri. jflecken@wustl.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Fleckenstein
mesh_terms: D000017:ABO Blood-Group System / Q000737:chemistry / Q000378:metabolism*; D000116:Acetylgalactosamine / Q000737:chemistry / Q000378:metabolism; D064113:CRISPR-Cas Systems; D060846:Cell Engineering; D002771:Cholera; D002772:Cholera Toxin / Q000302:isolation & purification / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D005677:G(M1) Ganglioside / Q000737:chemistry / Q000378:metabolism*; D005690:Galactose / Q000737:chemistry / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D011485:Protein Binding; D012720:Severity of Illness Index; D014734:Vibrio cholerae / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000017:ABO Blood-Group System; D005576:Colforsin; D005677:G(M1) Ganglioside; D002772:Cholera Toxin; D000242:Cyclic AMP; D000116:Acetylgalactosamine; D005690:Galactose