Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections
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 pa...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42572-0 |
| _version_ | 1797558175964069888 |
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| author | 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 Johan Malmström |
| author_facet | 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 Johan Malmström |
| author_sort | Alejandro Gomez Toledo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:26:45Z |
| format | Article |
| id | doaj.art-bce37cf8902b4d488654606c706f6c47 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:26:45Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-bce37cf8902b4d488654606c706f6c472023-11-20T10:09:24ZengNature PortfolioNature Communications2041-17232023-10-0114111610.1038/s41467-023-42572-0Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infectionsAlejandro Gomez Toledo0Eleni Bratanis1Erika Velásquez2Sounak Chowdhury3Berit Olofsson4James T. Sorrentino5Christofer Karlsson6Nathan E. Lewis7Jeffrey D. Esko8Mattias Collin9Oonagh Shannon10Johan Malmström11Division of Infection Medicine, Department of Clinical Sciences, Lund UniversityDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityIPSC Laboratory for CNS Disease Modeling, Department of Experimental Medical Sciences, Lund UniversityDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityBioinformatics and Systems Biology Graduate Program, University of California, San DiegoDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityDepartments of Pediatrics and Bioengineering, University of California, San DiegoDepartment of Cellular and Molecular Medicine, University of California, San DiegoDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityDivision of Infection Medicine, Department of Clinical Sciences, Lund UniversityAbstract 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.https://doi.org/10.1038/s41467-023-42572-0 |
| spellingShingle | 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 Johan Malmström Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections Nature Communications |
| title | Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| title_full | Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| title_fullStr | Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| title_full_unstemmed | Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| title_short | Pathogen-driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| title_sort | pathogen driven degradation of endogenous and therapeutic antibodies during streptococcal infections |
| url | https://doi.org/10.1038/s41467-023-42572-0 |
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