Letter

High-avidity IgA protects the intestine by enchaining growing bacteria

  • Nature volume 544, pages 498502 (27 April 2017)
  • doi:10.1038/nature22058
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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’)1,2,3. 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 densities4,5 (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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Acknowledgements

The authors would like to acknowledge the support of ScopeM (ETHZ), and the staff at the RCHCI and EPIC animal facilities. They would also like to thank members of the Hardt and Hapfelmeier groups, as well as A. J. Macpherson, S. Sunagawa, M. F. Freeman, C. Mueller, B. Stecher, K. Endt, M. Stecher, M. Bajagic and M. Ackermann for technical help and/or their comments on the manuscript. E.S. is supported by the Swiss National Science Foundation (SNF, Marie Heim-Vöglin award PMPDP3_158364 and Ambizione award PZ00P3_136742 to E.S.). W.-D.H. is supported by the SNF (310030_53074; Sinergia CRSII_154414/1), ETH Zurich (ETH-33 12-2) and the Novartis Freenovation Programme. D.R.B. acknowledges support from a Human Frontier Science Program Cross-Disciplinary Fellowship. E.B. is supported by the Excellence Scholarship and Opportunity Programme (ETH). R.S. acknowledges support from a Gordon and Betty Moore Foundation Marine Microbial Initiative Award (GBMF 3783). R.R.R. acknowledges support from the Swiss National Science Foundation (31003A_149769). T.V. is supported by a Deutsche Forschungsgemeinschaft postdoctoral fellowship (grant VO 2273/1-1) and M.E.S. by the Swedish Research Council (grants 2012-262 and 2015-00635).

Author information

Author notes

    • Kathrin Moor
    •  & Costanza Casiraghi

    Present addresses: Center for Dental Medicine, University of Zürich, Zürich, Switzerland (K.M.); Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy (C.C.).

    • Douglas R. Brumley
    • , Wolf-Dietrich Hardt
    •  & Emma Slack

    These authors contributed equally to this work.

Affiliations

  1. Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland

    • Kathrin Moor
    • , Médéric Diard
    • , Mikael E. Sellin
    • , Boas Felmy
    • , Sandra Y. Wotzka
    • , Albulena Toska
    • , Erik Bakkeren
    • , Markus Arnoldini
    • , Tom Völler
    • , Antonio Lanzavecchia
    • , Wolf-Dietrich Hardt
    •  & Emma Slack
  2. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75124 Uppsala, Sweden

    • Mikael E. Sellin
  3. Laboratoire Jean Perrin (UMR 8237), CNRS - UPMC, 75005 Paris, France

    • Florence Bansept
    •  & Claude Loverdo
  4. Department of Environmental Systems Science, ETH Zurich, Zürich, Switzerland

    • Alma Dal Co
  5. Department of Environmental Microbiology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland

    • Alma Dal Co
  6. Humabs BioMed SA, 6500 Bellinzona, Switzerland

    • Andrea Minola
    • , Gloria Agatic
    •  & Davide Corti
  7. Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland

    • Blanca Fernandez-Rodriguez
    • , Sonia Barbieri
    • , Luca Piccoli
    • , Costanza Casiraghi
    •  & Antonio Lanzavecchia
  8. Institute of Integrative Biology, ETH Zürich, 8092 Zürich, Switzerland

    • Roland R. Regoes
  9. Institute of Environmental Engineering, Department of Civil, Environmental, and Geomatic Engineering, ETH Zürich, 8093 Zürich, Switzerland

    • Roman Stocker
    •  & Douglas R. Brumley
  10. School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia

    • Douglas R. Brumley

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Contributions

K.M., M.D., M.E.S., E.B., B.F., S.Y.W., A.T., W.-D.H and E.S. designed, performed and analysed experiments. M.A., A.D.C. and T.V. carried out image analysis. A.M., B.F.-R., G.A., S.B., L.P., C.C., D.C. and A.L. generated human monoclonal and mouse recombinant antibodies. F.B., C.L., and R.R.R. devised models and mathematically analysed barcoded-strain experiments. R.S. and D.R.B. devised and developed the model for planktonic bacteria population dynamics and wrote the extended discussion in the Supplementary Information. The paper was written by E.S. with support from W.-D.H. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Reviewer Information Nature thanks A. Baumler, A. Camilli, S. Fagarasan and A. Smith for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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    Supplementary Information

    This file contains a Supplementary Discussion and Supplementary Tables 1-2.

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