title: High-avidity IgA protects the intestine by enchaining growing bacteria.
abstract: Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions with the gut tissues ('immune exclusion'). IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (≥108non-motile bacteria per gram). In typical infections, much lower densities (100-107colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo: IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo. Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance.
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Moor
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Médéric
authors.initials: M
authors.lastname: Diard
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.|Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75124 Uppsala, Sweden.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Wotzka
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Albulena
authors.initials: A
authors.lastname: Toska
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Erik
authors.initials: E
authors.lastname: Bakkeren
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Arnoldini
authors.affiliation: Laboratoire Jean Perrin (UMR 8237), CNRS - UPMC, 75005 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bansept
authors.affiliation: Department of Environmental Systems Science, ETH Zurich, Zürich, Switzerland.|Department of Environmental Microbiology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland.
authors.forename: Alma Dal
authors.initials: AD
authors.lastname: Co
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Tom
authors.initials: T
authors.lastname: Völler
authors.affiliation: Humabs BioMed SA, 6500 Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Minola
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Blanca
authors.initials: B
authors.lastname: Fernandez-Rodriguez
authors.affiliation: Humabs BioMed SA, 6500 Bellinzona, Switzerland.
authors.forename: Gloria
authors.initials: G
authors.lastname: Agatic
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Barbieri
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Piccoli
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Costanza
authors.initials: C
authors.lastname: Casiraghi
authors.affiliation: Humabs BioMed SA, 6500 Bellinzona, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.|Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.affiliation: Institute of Integrative Biology, ETH Zürich, 8092 Zürich, Switzerland.
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.affiliation: Laboratoire Jean Perrin (UMR 8237), CNRS - UPMC, 75005 Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Loverdo
authors.affiliation: Institute of Environmental Engineering, Department of Civil, Environmental, and Geomatic Engineering, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Stocker
authors.affiliation: Institute of Environmental Engineering, Department of Civil, Environmental, and Geomatic Engineering, ETH Zürich, 8093 Zürich, Switzerland.|School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Brumley
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
authors.affiliation: Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D001422:Bacterial Adhesion; D001428:Bacterial Vaccines; D002432:Cecum / Q000276:immunology / Q000382:microbiology; D015169:Colony Count, Microbial; D003227:Conjugation, Genetic; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000382:microbiology*; D008297:Male; D051379:Mice; D010957:Plasmids / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development* / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D001428:Bacterial Vaccines; D007070:Immunoglobulin A