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Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow

Author

Listed:
  • Alejandro Gomez Toledo

    (Lund University)

  • Sounak Chowdhury

    (Lund University)

  • Elisabeth Hjortswang

    (Lund University)

  • James T. Sorrentino

    (University of California)

  • Nathan E. Lewis

    (University of California)

  • Anna Bläckberg

    (Lund University)

  • Simon Ekström

    (BioMS)

  • Sven Kjellström

    (BioMS)

  • Arman Izadi

    (Lund University)

  • Berit Olofsson

    (Lund University)

  • Pontus Nordenfelt

    (Lund University)

  • Lars Malmström

    (Lund University)

  • Magnus Rasmussen

    (Lund University)

  • Johan Malmström

    (Lund University
    BioMS)

Abstract

This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and systems serology to characterize human antibodies in clinical samples. This strategy involves using antibodies circulating in plasma to affinity-enrich antigenic proteins in biochemically fractionated pools of bacterial proteins, followed by their identification and quantification using mass spectrometry. A selected subset of the identified antigens is then expressed recombinantly to isolate antigen-specific IgG, followed by characterization of the structural and functional properties of these antibodies. We focused on Group A streptococcus (GAS), a major human pathogen lacking an approved vaccine. The data shows that both healthy and GAS-infected individuals have circulating IgG against conserved streptococcal proteins, including toxins and virulence factors. The antigenic breadth of these antibodies remains relatively constant across healthy individuals but changes considerably in GAS bacteremia. Moreover, antigen-specific IgG analysis reveals individual variation in titers, subclass distributions, and Fc-signaling capacity, despite similar epitope and Fc-glycosylation patterns. Finally, we show that GAS antibodies may cross-react with Streptococcus dysgalactiae (SD), a bacterial pathogen that occupies similar niches and causes comparable infections. Collectively, our results highlight the complexity of GAS-specific antibody responses and the versatility of our methodology to characterize immune responses to bacterial pathogens.

Suggested Citation

  • Alejandro Gomez Toledo & Sounak Chowdhury & Elisabeth Hjortswang & James T. Sorrentino & Nathan E. Lewis & Anna Bläckberg & Simon Ekström & Sven Kjellström & Arman Izadi & Berit Olofsson & Pontus Nord, 2025. "Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57170-5
    DOI: 10.1038/s41467-025-57170-5
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    References listed on IDEAS

    as
    1. Nigel M. Stapleton & Jan Terje Andersen & Annette M. Stemerding & Stefania P. Bjarnarson & Ruurd C. Verheul & Jacoline Gerritsen & Yixian Zhao & Marion Kleijer & Inger Sandlie & Masja de Haas & Ingile, 2011. "Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    2. Arman Izadi & Yasaman Karami & Eleni Bratanis & Sebastian Wrighton & Hamed Khakzad & Maria Nyblom & Berit Olofsson & Lotta Happonen & Di Tang & Martin Sundwall & Magdalena Godzwon & Yashuan Chao & Ale, 2024. "The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Lotta Happonen & Simon Hauri & Gabriel Svensson Birkedal & Christofer Karlsson & Therese Neergaard & Hamed Khakzad & Pontus Nordenfelt & Mats Wikström & Magdalena Wisniewska & Lars Björck & Lars Malms, 2019. "A quantitative Streptococcus pyogenes–human protein–protein interaction map reveals localization of opsonizing antibodies," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    4. Ouli Xie & Cameron Zachreson & Gerry Tonkin-Hill & David J. Price & Jake A. Lacey & Jacqueline M. Morris & Malcolm I. McDonald & Asha C. Bowen & Philip M. Giffard & Bart J. Currie & Jonathan R. Carape, 2024. "Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
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