Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis

Erin A. Catton; Daniel A. Bonsor; Carolina Herrera; Margaretha Stålhammar-Carlemalm; Mykola Lyndin; Claire E. Turner; Jo Soden; Jos A. G. van Strijp; Bernhard B. Singer; Nina M. van Sorge; Gunnar Lindahl; Alex J. McCarthy

doi:https://doi.org/10.1038/s41467-023-37732-1

Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis

Erin A. Catton, Daniel A. Bonsor, Carolina Herrera, Margaretha Stålhammar-Carlemalm, Mykola Lyndin, Claire E. Turner, Jo Soden, Jos A. G. van Strijp, Bernhard B. Singer, Nina M. van Sorge, Gunnar Lindahl, Alex J. McCarthy

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Life-threatening bacterial infections in women after childbirth, known as puerperal sepsis, resulted in classical epidemics and remain a global health problem. While outbreaks of puerperal sepsis have been ascribed to Streptococcus pyogenes, little is known about disease mechanisms. Here, we show that the bacterial R28 protein, which is epidemiologically associated with outbreaks of puerperal sepsis, specifically targets the human receptor CEACAM1. This interaction triggers events that would favor the development of puerperal sepsis, including adhesion to cervical cells, suppression of epithelial wound repair and subversion of innate immune responses. High-resolution structural analysis showed that an R28 domain with IgI3-like fold binds to the N-terminal domain of CEACAM1. Together, these findings demonstrate that a single adhesin-receptor interaction can drive the pathogenesis of bacterial sepsis and provide molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.

Original language	English
Article number	2275
Pages (from-to)	2275
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37732-1
Publication status	Published - Dec 2023

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Catton, E. A., Bonsor, D. A., Herrera, C., Stålhammar-Carlemalm, M., Lyndin, M., Turner, C. E., Soden, J., van Strijp, J. A. G., Singer, B. B., van Sorge, N. M., Lindahl, G., & McCarthy, A. J. (2023). Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis. Nature communications, 14(1), 2275. Article 2275. https://doi.org/10.1038/s41467-023-37732-1

@article{20f141fdf99c4c4ebfa3e5b70379f37f,

title = "Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis",

abstract = "Life-threatening bacterial infections in women after childbirth, known as puerperal sepsis, resulted in classical epidemics and remain a global health problem. While outbreaks of puerperal sepsis have been ascribed to Streptococcus pyogenes, little is known about disease mechanisms. Here, we show that the bacterial R28 protein, which is epidemiologically associated with outbreaks of puerperal sepsis, specifically targets the human receptor CEACAM1. This interaction triggers events that would favor the development of puerperal sepsis, including adhesion to cervical cells, suppression of epithelial wound repair and subversion of innate immune responses. High-resolution structural analysis showed that an R28 domain with IgI3-like fold binds to the N-terminal domain of CEACAM1. Together, these findings demonstrate that a single adhesin-receptor interaction can drive the pathogenesis of bacterial sepsis and provide molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.",

author = "Catton, {Erin A.} and Bonsor, {Daniel A.} and Carolina Herrera and Margaretha St{\aa}lhammar-Carlemalm and Mykola Lyndin and Turner, {Claire E.} and Jo Soden and {van Strijp}, {Jos A. G.} and Singer, {Bernhard B.} and {van Sorge}, {Nina M.} and Gunnar Lindahl and McCarthy, {Alex J.}",

note = "Funding Information: This manuscript is dedicated to the life of Bernhard B. Singer who passed away in January 2023 after the experimental part of this work and drafting of the manuscript was completed. We would like to thank the CDC (USA) and Shiranee Sriskandan (Imperial College London) for access to clinical S. pyogenes strains. We thank the Department of Surgery and Cancer and the Department of Obstetrics and Gynaecology at St. Mary{\textquoteright}s Hospital, Imperial College for their assistance in obtaining human tissue. We thank York Tissue Bank, York Biomedical Research Institute, University of York, UK for access to human ecto-cervical explants. We thank staff at the Flow Cytometry Facility and High-Throughput Single Cell Analysis (HTSCA) Facility for technical assistance. We thank Carla J.C. de Haas, Piet Aerts, Kok P.M. van Kessel (UMC Utrecht, Utrecht, The Netherlands), and Birgit Maranca-H{\"u}wel, B{\"a}rbel Gobs-Hevelke (University of Duisburg-Essen, Germany) for technical support. We thank the staff of Beamlines 12-2 and ID23-D at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, respectively, for support in data collection. This work was supported by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under Grant Agreement 700862 (A.J.M. and J.A.G.V.S.), the Medical Research Council through the Doctoral Training Award MR/N014103/ to Imperial College London (E.A.C. and A.J.M.), the Biotechnology and Biological Sciences Research Council award BB/V006495/1 (A.J.M.), Royal Society Research Grant RGS\R1\201044 (A.J.M.), Deutsche Forschungsgemeinschaft DFG grant SI-1558/6-1 (B.B.S.), The Swedish Research Council grant K2011-56X-09490-21-6 (G.L.), a Vidi grant (91713303) from the Dutch Research Council for Health Research and Development (ZonMW; N.M.v.S.), and The Foundation Olle Engkvist Byggm{\"a}stare (G.L.). Funding Information: This manuscript is dedicated to the life of Bernhard B. Singer who passed away in January 2023 after the experimental part of this work and drafting of the manuscript was completed. We would like to thank the CDC (USA) and Shiranee Sriskandan (Imperial College London) for access to clinical S. pyogenes strains. We thank the Department of Surgery and Cancer and the Department of Obstetrics and Gynaecology at St. Mary{\textquoteright}s Hospital, Imperial College for their assistance in obtaining human tissue. We thank York Tissue Bank, York Biomedical Research Institute, University of York, UK for access to human ecto-cervical explants. We thank staff at the Flow Cytometry Facility and High-Throughput Single Cell Analysis (HTSCA) Facility for technical assistance. We thank Carla J.C. de Haas, Piet Aerts, Kok P.M. van Kessel (UMC Utrecht, Utrecht, The Netherlands), and Birgit Maranca-H{\"u}wel, B{\"a}rbel Gobs-Hevelke (University of Duisburg-Essen, Germany) for technical support. We thank the staff of Beamlines 12-2 and ID23-D at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, respectively, for support in data collection. This work was supported by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under Grant Agreement 700862 (A.J.M. and J.A.G.V.S.), the Medical Research Council through the Doctoral Training Award MR/N014103/ to Imperial College London (E.A.C. and A.J.M.), the Biotechnology and Biological Sciences Research Council award BB/V006495/1 (A.J.M.), Royal Society Research Grant RGS\R1\201044 (A.J.M.), Deutsche Forschungsgemeinschaft DFG grant SI-1558/6-1 (B.B.S.), The Swedish Research Council grant K2011-56X-09490-21-6 (G.L.), a Vidi grant (91713303) from the Dutch Research Council for Health Research and Development (ZonMW; N.M.v.S.), and The Foundation Olle Engkvist Byggm{\"a}stare (G.L.). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "https://doi.org/10.1038/s41467-023-37732-1",

language = "English",

volume = "14",

pages = "2275",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Catton, EA, Bonsor, DA, Herrera, C, Stålhammar-Carlemalm, M, Lyndin, M, Turner, CE, Soden, J, van Strijp, JAG, Singer, BB, van Sorge, NM, Lindahl, G & McCarthy, AJ 2023, 'Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis', Nature communications, vol. 14, no. 1, 2275, pp. 2275. https://doi.org/10.1038/s41467-023-37732-1

TY - JOUR

T1 - Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis

AU - Catton, Erin A.

AU - Bonsor, Daniel A.

AU - Herrera, Carolina

AU - Stålhammar-Carlemalm, Margaretha

AU - Lyndin, Mykola

AU - Turner, Claire E.

AU - Soden, Jo

AU - van Strijp, Jos A. G.

AU - Singer, Bernhard B.

AU - van Sorge, Nina M.

AU - Lindahl, Gunnar

AU - McCarthy, Alex J.

N1 - Funding Information: This manuscript is dedicated to the life of Bernhard B. Singer who passed away in January 2023 after the experimental part of this work and drafting of the manuscript was completed. We would like to thank the CDC (USA) and Shiranee Sriskandan (Imperial College London) for access to clinical S. pyogenes strains. We thank the Department of Surgery and Cancer and the Department of Obstetrics and Gynaecology at St. Mary’s Hospital, Imperial College for their assistance in obtaining human tissue. We thank York Tissue Bank, York Biomedical Research Institute, University of York, UK for access to human ecto-cervical explants. We thank staff at the Flow Cytometry Facility and High-Throughput Single Cell Analysis (HTSCA) Facility for technical assistance. We thank Carla J.C. de Haas, Piet Aerts, Kok P.M. van Kessel (UMC Utrecht, Utrecht, The Netherlands), and Birgit Maranca-Hüwel, Bärbel Gobs-Hevelke (University of Duisburg-Essen, Germany) for technical support. We thank the staff of Beamlines 12-2 and ID23-D at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, respectively, for support in data collection. This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 700862 (A.J.M. and J.A.G.V.S.), the Medical Research Council through the Doctoral Training Award MR/N014103/ to Imperial College London (E.A.C. and A.J.M.), the Biotechnology and Biological Sciences Research Council award BB/V006495/1 (A.J.M.), Royal Society Research Grant RGS\R1\201044 (A.J.M.), Deutsche Forschungsgemeinschaft DFG grant SI-1558/6-1 (B.B.S.), The Swedish Research Council grant K2011-56X-09490-21-6 (G.L.), a Vidi grant (91713303) from the Dutch Research Council for Health Research and Development (ZonMW; N.M.v.S.), and The Foundation Olle Engkvist Byggmästare (G.L.). Funding Information: This manuscript is dedicated to the life of Bernhard B. Singer who passed away in January 2023 after the experimental part of this work and drafting of the manuscript was completed. We would like to thank the CDC (USA) and Shiranee Sriskandan (Imperial College London) for access to clinical S. pyogenes strains. We thank the Department of Surgery and Cancer and the Department of Obstetrics and Gynaecology at St. Mary’s Hospital, Imperial College for their assistance in obtaining human tissue. We thank York Tissue Bank, York Biomedical Research Institute, University of York, UK for access to human ecto-cervical explants. We thank staff at the Flow Cytometry Facility and High-Throughput Single Cell Analysis (HTSCA) Facility for technical assistance. We thank Carla J.C. de Haas, Piet Aerts, Kok P.M. van Kessel (UMC Utrecht, Utrecht, The Netherlands), and Birgit Maranca-Hüwel, Bärbel Gobs-Hevelke (University of Duisburg-Essen, Germany) for technical support. We thank the staff of Beamlines 12-2 and ID23-D at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, respectively, for support in data collection. This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 700862 (A.J.M. and J.A.G.V.S.), the Medical Research Council through the Doctoral Training Award MR/N014103/ to Imperial College London (E.A.C. and A.J.M.), the Biotechnology and Biological Sciences Research Council award BB/V006495/1 (A.J.M.), Royal Society Research Grant RGS\R1\201044 (A.J.M.), Deutsche Forschungsgemeinschaft DFG grant SI-1558/6-1 (B.B.S.), The Swedish Research Council grant K2011-56X-09490-21-6 (G.L.), a Vidi grant (91713303) from the Dutch Research Council for Health Research and Development (ZonMW; N.M.v.S.), and The Foundation Olle Engkvist Byggmästare (G.L.). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Life-threatening bacterial infections in women after childbirth, known as puerperal sepsis, resulted in classical epidemics and remain a global health problem. While outbreaks of puerperal sepsis have been ascribed to Streptococcus pyogenes, little is known about disease mechanisms. Here, we show that the bacterial R28 protein, which is epidemiologically associated with outbreaks of puerperal sepsis, specifically targets the human receptor CEACAM1. This interaction triggers events that would favor the development of puerperal sepsis, including adhesion to cervical cells, suppression of epithelial wound repair and subversion of innate immune responses. High-resolution structural analysis showed that an R28 domain with IgI3-like fold binds to the N-terminal domain of CEACAM1. Together, these findings demonstrate that a single adhesin-receptor interaction can drive the pathogenesis of bacterial sepsis and provide molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.

AB - Life-threatening bacterial infections in women after childbirth, known as puerperal sepsis, resulted in classical epidemics and remain a global health problem. While outbreaks of puerperal sepsis have been ascribed to Streptococcus pyogenes, little is known about disease mechanisms. Here, we show that the bacterial R28 protein, which is epidemiologically associated with outbreaks of puerperal sepsis, specifically targets the human receptor CEACAM1. This interaction triggers events that would favor the development of puerperal sepsis, including adhesion to cervical cells, suppression of epithelial wound repair and subversion of innate immune responses. High-resolution structural analysis showed that an R28 domain with IgI3-like fold binds to the N-terminal domain of CEACAM1. Together, these findings demonstrate that a single adhesin-receptor interaction can drive the pathogenesis of bacterial sepsis and provide molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.

UR - http://www.scopus.com/inward/record.url?scp=85153430593&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41467-023-37732-1

DO - https://doi.org/10.1038/s41467-023-37732-1

M3 - Article

C2 - 37080973

SN - 2041-1723

VL - 14

SP - 2275

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2275

ER -

Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis

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