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

Alejandro Gomez Toledo, Sounak Chowdhury, Elisabeth Hjortswang, James T. Sorrentino, Nathan E. Lewis, Anna Bläckberg, Simon Ekström, Sven Kjellström, Arman Izadi, Berit Olofsson, Pontus Nordenfelt, Lars Malmström, Magnus Rasmussen and Johan Malmström ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57170-5

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