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Nature. 2017 Apr 27;544(7651):498-502. doi: 10.1038/nature22058. Epub 2017 Apr 12.

High-avidity IgA protects the intestine by enchaining growing bacteria.

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Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75124 Uppsala, Sweden.
Laboratoire Jean Perrin (UMR 8237), CNRS - UPMC, 75005 Paris, France.
Department of Environmental Systems Science, ETH Zurich, Zürich, Switzerland.
Department of Environmental Microbiology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland.
Humabs BioMed SA, 6500 Bellinzona, Switzerland.
Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
Institute of Integrative Biology, ETH Zürich, 8092 Zürich, Switzerland.
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.


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 (≥108 non-motile bacteria per gram). In typical infections, much lower densities (100-107 colony-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.

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