Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2017-08-14
Date Acceptance
2017-06-27
Citation
PLOS Pathogens, 2017, 13 (8), pp.1-29
ISSN
1553-7366
Publisher
Public Library of Science
Start Page
1
End Page
29
Journal / Book Title
PLOS Pathogens
Volume
13
Issue
8
Copyright Statement
© 2017 Lynskey et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
License URL
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Identifier
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006493
Grant Number
103197/Z/13/Z
MR/L008610/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
GROUP-A STREPTOCOCCI
GROUP-B STREPTOCOCCI
ENDOTHELIAL-CELLS
INNATE IMMUNITY
STAPHYLOCOCCUS-AUREUS
C4B-BINDING PROTEIN
VACCINE DEVELOPMENT
CLASSICAL PATHWAY
INFECTED MICE
FACTOR-H
Adhesins, Bacterial
Animals
Blotting, Western
Complement Activation
Endopeptidases
Humans
Immune Evasion
Mice
Mice, Inbred C57BL
Polymerase Chain Reaction
Streptococcal Infections
Streptococcus pyogenes
Animals
Mice, Inbred C57BL
Humans
Mice
Streptococcus pyogenes
Streptococcal Infections
Endopeptidases
Adhesins, Bacterial
Blotting, Western
Polymerase Chain Reaction
Complement Activation
Immune Evasion
Virology
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status
Published
Article Number
e1006493
Date Publish Online
2017-08-14