Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase
| Autor: | Shiranee Sriskandan, Nicola N. Lynskey, Damien Calay, Mark Reglinski, Marina Botto, Matthew K. Siggins, Justin C Mason |
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| Přispěvatelé: | Wellcome Trust, Medical Research Council (MRC) |
| Rok vydání: | 2017 |
| Předmět: |
Bacterial Diseases
0301 basic medicine Physiology Neutrophils Complement System VACCINE DEVELOPMENT Pathogenesis Pathology and Laboratory Medicine medicine.disease_cause Biochemistry Polymerase Chain Reaction White Blood Cells Mice Complement inhibitor Animal Cells CLASSICAL PATHWAY 1108 Medical Microbiology Immune Physiology Medicine and Health Sciences INFECTED MICE lcsh:QH301-705.5 Complement Activation GROUP-B STREPTOCOCCI Immune System Proteins GROUP-A STREPTOCOCCI C4b-binding protein Streptococcus pyogenes/immunology Animal Models Bacterial Pathogens Body Fluids 3. Good health Antibody opsonization Infectious Diseases Blood Experimental Organism Systems Medical Microbiology 1107 Immunology Cellular Types Pathogens Anatomy Life Sciences & Biomedicine Research Article 0605 Microbiology lcsh:Immunologic diseases. Allergy FACTOR-H Streptococcus pyogenes Immune Cells Blotting Western Immunology Mouse Models Biology Research and Analysis Methods Microbiology C4B-BINDING PROTEIN 03 medical and health sciences Classical complement pathway Model Organisms Streptococcal Infections Virology Endopeptidases Genetics medicine Animals Humans Immune Evasion/immunology Streptococcal Infections/immunology Adhesins Bacterial Microbial Pathogens Molecular Biology Adhesins Bacterial/immunology STAPHYLOCOCCUS-AUREUS Immune Evasion Blood Cells Science & Technology Innate immune system Bacteria Complement Activation/immunology Organisms Biology and Life Sciences Proteins Streptococcus Cell Biology ENDOTHELIAL-CELLS C3-convertase Complement system Mice Inbred C57BL 030104 developmental biology lcsh:Biology (General) Immune System INNATE IMMUNITY Parasitology lcsh:RC581-607 Endopeptidases/immunology |
| Zdroj: | PLoS Pathogens, Vol 13, Iss 8, p e1006493 (2017) Lynskey, N N, Reglinski, M, Calay, D, Siggins, M K, Mason, J C, Botto, M & Sriskandan, S 2017, ' Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase ', PLoS Pathogens, vol. 13, no. 8, e1006493 . https://doi.org/10.1371/journal.ppat.1006493 PLoS Pathogens |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1006493 |
| Popis: | The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase. Cleavage of C3a by ScpA resulted in disruption of human neutrophil activation, phagocytosis and chemotaxis, while cleavage of C3 generated abnormally-sized C3a and C3b moieties with impaired function, in particular reducing C3 deposition on the bacterial surface. Despite clear effects on human complement, expression of ScpA reduced clearance of group A streptococci in vivo in wildtype and C5 deficient mice, and promoted systemic bacterial dissemination in mice that lacked both C3 and C5, suggesting an additional complement-independent role for ScpA in streptococcal pathogenesis. ScpA was shown to mediate streptococcal adhesion to both human epithelial and endothelial cells, consistent with a role in promoting bacterial invasion within the host. Taken together, these data show that ScpA is a multi-functional virulence factor with both complement-dependent and independent roles in streptococcal pathogenesis. Author summary The complement pathway is critical in the innate immune response to bacterial pathogens. It consists of a self-perpetuating proteolytic cascade initiated via three distinct pathways that converge at the central complement protein, C3. Pathogens must evade complement-mediated immunity to cause disease, and inactivation of the C3 protein can dampen all effectors of this pathway. Streptococcal species are the causative agents of an array of infections ranging from the benign to lethal. Using the human pathogen Group A Streptococcus as a representative species, we show that the enzyme ScpA, which is conserved amongst the pyogenic streptococci, cleaves human C3a and also C3, releasing abnormally sized and functionally-impaired fragments. As a result, invading streptococci were less well opsonized and host immune cells not properly activated, reducing bacterial phagocytosis and clearance. Despite manifest in vitro activity against complement factors and human neutrophils, ScpA was still able to contribute to systemic bacterial spread in mice lacking C3 and C5. ScpA was also demonstrated to mediate streptococcal adhesion to both epithelial and endothelial cells, which may enhance bacterial systemic spread. Our study highlights the likely importance of both complement-independent and complement-dependent roles for ScpA in streptococcal pathogenesis. |
| Databáze: | OpenAIRE |
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