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

Toledo, Alejandro Gomez LU ; Bratanis, Eleni LU ; Velásquez, Erika LU ; Chowdhury, Sounak LU ; Olofsson, Berit LU orcid ; Sorrentino, James T ; Karlsson, Christofer LU ; Lewis, Nathan E ; Esko, Jeffrey D and Collin, Mattias LU orcid , et al. (2023) In Nature Communications 14. p.1-16
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
article number
6693
pages
1 - 16
publisher
Nature Publishing Group
external identifiers
  • scopus:85174676240
  • pmid:37872209
ISSN
2041-1723
DOI
10.1038/s41467-023-42572-0
language
English
LU publication?
yes
additional info
© 2023. Springer Nature Limited.
id
58b4227d-6d78-4b76-a59d-f1d358d16f3f
date added to LUP
2023-10-25 18:06:57
date last changed
2024-04-15 17:37:19
@article{58b4227d-6d78-4b76-a59d-f1d358d16f3f,
  abstract     = {{<p>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.</p>}},
  author       = {{Toledo, Alejandro Gomez and Bratanis, Eleni and Velásquez, Erika and Chowdhury, Sounak and Olofsson, Berit and Sorrentino, James T and Karlsson, Christofer and Lewis, Nathan E and Esko, Jeffrey D and Collin, Mattias and Shannon, Oonagh and Malmström, Johan}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{10}},
  pages        = {{1--16}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-42572-0}},
  doi          = {{10.1038/s41467-023-42572-0}},
  volume       = {{14}},
  year         = {{2023}},
}