Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections

Alejandro Gomez Toledo, Eleni Bratanis, Erika Velásquez, Sounak Chowdhury, Berit Olofsson, James T. Sorrentino, Christofer Karlsson, Nathan E. Lewis, Jeffrey D. Esko, Mattias Collin, Oonagh Shannon and Johan Malmström ()
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Alejandro Gomez Toledo: Lund University
Eleni Bratanis: Lund University
Erika Velásquez: Lund University
Sounak Chowdhury: Lund University
Berit Olofsson: Lund University
James T. Sorrentino: University of California, San Diego
Christofer Karlsson: Lund University
Nathan E. Lewis: University of California, San Diego
Jeffrey D. Esko: University of California, San Diego
Mattias Collin: Lund University
Oonagh Shannon: Lund University
Johan Malmström: Lund University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Group A streptococcus (GAS) is a major bacterial pathogen responsible for both local and systemic infections in humans. The molecular mechanisms that contribute to disease heterogeneity remain poorly understood. Here we show that the transition from a local to a systemic GAS infection is paralleled by pathogen-driven alterations in IgG homeostasis. Using animal models and a combination of sensitive proteomics and glycoproteomics readouts, we documented the progressive accumulation of IgG cleavage products in plasma, due to extensive enzymatic degradation triggered by GAS infection in vivo. The level of IgG degradation was modulated by the route of pathogen inoculation, and mechanistically linked to the combined activities of the bacterial protease IdeS and the endoglycosidase EndoS, upregulated during infection. Importantly, we show that these virulence factors can alter the structure and function of exogenous therapeutic IgG in vivo. These results shed light on the role of bacterial virulence factors in shaping GAS pathogenesis, and potentially blunting the efficacy of antimicrobial therapies.

Date: 2023
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DOI: 10.1038/s41467-023-42572-0

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