期刊论文详细信息
Journal of Biomedical Science
Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes
Research
Bhavya Chakrakodi1  Mattias Svensson1  Anna Norrby-Teglund1  Kirsten Moll1  Ole Hyldegaard2  Michael Nekludov3  Per Arnell4  Steinar Skrede5  Thomas Sura6  Patience Shumba7  Lea A. Tölken7  Nikolai Siemens7  Jörn Hoßmann8  Katharina J. Hoff9 
[1] Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden;Department of Anaesthesia, Head and Orthopedic Center, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark;Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;Department of Anaesthesia, Surgical Services and Intensive Care, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden;Department of Anaesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden;Department of Medicine, Haukeland University Hospital, Bergen, Norway;Department of Clinical Science, University of Bergen, Bergen, Norway;Department of Microbial Proteomics, Institute of Microbiology, University of Greifswald, Greifswald, Germany;Department of Molecular Genetics and Infection Biology, University of Greifswald, Greifswald, Germany;Helmholtz Center for Infection Research, Brunswick, Germany;Institute of Mathematics and Computer Science, University of Greifswald, Greifswald, Germany;
关键词: Streptococcus pyogenes;    Necrotizing soft tissue infections;    SpeB;    Neutrophils;   
DOI  :  10.1186/s12929-023-00947-x
 received in 2023-02-24, accepted in 2023-07-03,  发布年份 2023
来源: Springer
PDF
【 摘 要 】

BackgroundStreptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase.MethodsBacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry.ResultsHere, we identify another strategy resulting in SpeB-negative variants, namely reversible abrogation of SpeB secretion triggered by neutrophil effector molecules. Analysis of NSTI patient tissue biopsies revealed that tissue inflammation, neutrophil influx, and degranulation positively correlate with increasing frequency of SpeB-negative GAS clones. Using single colony proteomics, we show that GAS isolated directly from tissue express but do not secrete SpeB. Once the tissue pressure is lifted, GAS regain SpeB secreting function. Neutrophils were identified as the main immune cells responsible for the observed phenotype. Subsequent analyses identified hydrogen peroxide and hypochlorous acid as reactive agents driving this phenotypic GAS adaptation to the tissue environment. SpeB-negative GAS show improved survival within neutrophils and induce increased degranulation.ConclusionsOur findings provide new information about GAS fitness and heterogeneity in the soft tissue milieu and provide new potential targets for therapeutic intervention in NSTIs.

【 授权许可】

CC BY   
© The Author(s) 2023

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