title: Selection for a CEACAM receptor-specific binding phenotype during Neisseria gonorrhoeae infection of the human genital tract.
abstract: Infections by Neisseria gonorrhoeae are increasingly common, are often caused by antibiotic-resistant strains, and can result in serious and lasting sequelae, prompting the reemergence of gonococcal disease as a leading global health concern. N. gonorrhoeae is a human-restricted pathogen that primarily colonizes urogenital mucosal surfaces. Disease progression varies greatly between the sexes: men usually present with symptomatic infection characterized by a painful purulent urethral discharge, while in women, the infection is often asymptomatic, with the most severe pathology occurring when the bacteria ascend from the lower genital tract into the uterus and fallopian tubes. Classical clinical studies demonstrated that clinically infectious strains uniformly express Opa adhesins; however, their specificities were unknown at the time. While in vitro studies have since identified CEACAM proteins as the primary target of Opa proteins, the gonococcal specificity for this human family of receptors has not been addressed in the context of natural infection. In this study, we characterize a collection of low-passage-number clinical-specimen-derived N. gonorrhoeae isolates for Opa expression and assess their CEACAM-binding profiles. We report marked in vivo selection for expression of phase-variable Opa proteins that bind CEACAM1 and CEACAM5 but selection against expression of Opa variants that bind to the neutrophil-restricted decoy receptor CEACAM3. This is the first study showing phenotypic selection for distinct CEACAM-binding phenotypes in vivo, and it supports the opposing functions of CEACAMs that facilitate infection versus driving inflammation within the genital tract.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Sintsova
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: MacDonald
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Mumtaz
authors.initials: M
authors.lastname: Virji
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada scott.gray.owen@utoronto.ca.
authors.forename: Scott D
authors.identifier: http://orcid.org/0000-0002-1477-3616
authors.initials: SD
authors.lastname: Gray-Owen
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D001422:Bacterial Adhesion / Q000235:genetics*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D002584:Cervix Uteri / Q000382:microbiology; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006069:Gonorrhea / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D009344:Neisseria gonorrhoeae / Q000276:immunology / Q000302:isolation & purification; D009504:Neutrophils / Q000276:immunology; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D014521:Urethra / Q000382:microbiology
chemical_list: D018829:Adhesins, Bacterial; D000942:Antigens, Bacterial; D015703:Antigens, CD; D001425:Bacterial Outer Membrane Proteins; C069847:CD66 antigens; C075729:CEACAM3 protein, human; C527875:CEACAM5 protein, human; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D020033:Protein Isoforms; C090348:Opa protein, Neisseria