Streptococcus pyogenes Forms Serotype- and Local Environment-Dependent Interspecies Protein Complexes
Chowdhury, Sounak LU ; Khakzad, Hamed ; Bergdahl, Gizem Ertürk LU ; Lood, Rolf LU ; Ekstrom, Simon LU ; Linke, Dirk ; Malmström, Lars LU ; Happonen, Lotta LU and Malmström, Johan LU
(2021)
In mSystems
6(5).
p.1-19
- Abstract
Streptococcus pyogenes is known to cause both mucosal and systemic infections in humans. In this study, we used a combination of quantitative and structural mass spectrometry techniques to determine the composition and structure of the interaction network formed between human plasma proteins and the surfaces of different S. pyogenes serotypes. Quantitative network analysis revealed that S. pyogenes forms serotype-specific interaction networks that are highly dependent on the domain arrangement of the surface-attached M protein. Subsequent structural mass spectrometry analysis and computational modeling of one of the M proteins, M28, revealed that the network structure changes across different host microenvironments. We report that M28... (More)
Streptococcus pyogenes is known to cause both mucosal and systemic infections in humans. In this study, we used a combination of quantitative and structural mass spectrometry techniques to determine the composition and structure of the interaction network formed between human plasma proteins and the surfaces of different S. pyogenes serotypes. Quantitative network analysis revealed that S. pyogenes forms serotype-specific interaction networks that are highly dependent on the domain arrangement of the surface-attached M protein. Subsequent structural mass spectrometry analysis and computational modeling of one of the M proteins, M28, revealed that the network structure changes across different host microenvironments. We report that M28 binds secretory IgA via two separate binding sites with high affinity in saliva. During vascular leakage mimicked by increasing plasma concentrations in saliva, the binding of secretory IgA was replaced by the binding of monomeric IgA and C4b-binding protein (C4BP). This indicates that an upsurge of C4BP in the local microenvironment due to damage to the mucosal membrane drives the binding of C4BP and monomeric IgA to M28. These results suggest that S. pyogenes has evolved to form microenvironment-dependent host-pathogen protein complexes to combat human immune surveillance during both mucosal and systemic infections. IMPORTANCE Streptococcus pyogenes (group A Streptococcus [GAS]), is a human-specific Gram-positive bacterium. Each year, the bacterium affects 700 million people globally, leading to 160,000 deaths. The clinical manifestations of S. pyogenes are diverse, ranging from mild and common infections like tonsillitis and impetigo to life-threatening systemic conditions such as sepsis and necrotizing fasciitis. S. pyogenes expresses multiple virulence factors on its surface to localize and initiate infections in humans. Among all these expressed virulence factors, the M protein is the most important antigen. In this study, we perform an in-depth characterization of the human protein interactions formed around one of the foremost human pathogens. This strategy allowed us to decipher the protein interaction networks around different S. pyogenes strains on a global scale and to compare and visualize how such interactions are mediated by M proteins.
(Less)
- author
- Chowdhury, Sounak
LU
; Khakzad, Hamed
; Bergdahl, Gizem Ertürk
LU
; Lood, Rolf
LU
; Ekstrom, Simon
LU
; Linke, Dirk
; Malmström, Lars
LU
; Happonen, Lotta
LU
and Malmström, Johan
LU
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- mSystems
- volume
- 6
- issue
- 5
- article number
- e0027121
- pages
- 1 - 19
- publisher
- American Society for Microbiology
- external identifiers
-
- scopus:85116939114
- pmid:34581598
- ISSN
- 2379-5077
- DOI
- 10.1128/mSystems.00271-21
- language
- English
- LU publication?
- yes
- id
- a519fd2b-d390-4983-b47a-f337e72f8497
- date added to LUP
- 2021-10-04 09:36:35
- date last changed
- 2024-04-06 09:49:20
@article{a519fd2b-d390-4983-b47a-f337e72f8497,
abstract = {{<p>Streptococcus pyogenes is known to cause both mucosal and systemic infections in humans. In this study, we used a combination of quantitative and structural mass spectrometry techniques to determine the composition and structure of the interaction network formed between human plasma proteins and the surfaces of different S. pyogenes serotypes. Quantitative network analysis revealed that S. pyogenes forms serotype-specific interaction networks that are highly dependent on the domain arrangement of the surface-attached M protein. Subsequent structural mass spectrometry analysis and computational modeling of one of the M proteins, M28, revealed that the network structure changes across different host microenvironments. We report that M28 binds secretory IgA via two separate binding sites with high affinity in saliva. During vascular leakage mimicked by increasing plasma concentrations in saliva, the binding of secretory IgA was replaced by the binding of monomeric IgA and C4b-binding protein (C4BP). This indicates that an upsurge of C4BP in the local microenvironment due to damage to the mucosal membrane drives the binding of C4BP and monomeric IgA to M28. These results suggest that S. pyogenes has evolved to form microenvironment-dependent host-pathogen protein complexes to combat human immune surveillance during both mucosal and systemic infections. IMPORTANCE Streptococcus pyogenes (group A Streptococcus [GAS]), is a human-specific Gram-positive bacterium. Each year, the bacterium affects 700 million people globally, leading to 160,000 deaths. The clinical manifestations of S. pyogenes are diverse, ranging from mild and common infections like tonsillitis and impetigo to life-threatening systemic conditions such as sepsis and necrotizing fasciitis. S. pyogenes expresses multiple virulence factors on its surface to localize and initiate infections in humans. Among all these expressed virulence factors, the M protein is the most important antigen. In this study, we perform an in-depth characterization of the human protein interactions formed around one of the foremost human pathogens. This strategy allowed us to decipher the protein interaction networks around different S. pyogenes strains on a global scale and to compare and visualize how such interactions are mediated by M proteins.</p>}},
author = {{Chowdhury, Sounak and Khakzad, Hamed and Bergdahl, Gizem Ertürk and Lood, Rolf and Ekstrom, Simon and Linke, Dirk and Malmström, Lars and Happonen, Lotta and Malmström, Johan}},
issn = {{2379-5077}},
language = {{eng}},
number = {{5}},
pages = {{1--19}},
publisher = {{American Society for Microbiology}},
series = {{mSystems}},
title = {{Streptococcus pyogenes Forms Serotype- and Local Environment-Dependent Interspecies Protein Complexes}},
url = {{http://dx.doi.org/10.1128/mSystems.00271-21}},
doi = {{10.1128/mSystems.00271-21}},
volume = {{6}},
year = {{2021}},
}