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Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors.

Ermert, David LU ; Shaughnessy, Jutamas; Joeris, Thorsten LU ; Kaplan, Jakub LU ; Pang, Catherine J; Kurt-Jones, Evelyn A; Rice, Peter A; Ram, Sanjay and Blom, Anna LU (2015) In PLoS Pathogens 11(7).
Abstract
Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is an important human bacterial pathogen that can cause invasive infections. Once it colonizes its exclusively human host, GAS needs to surmount numerous innate immune defense mechanisms, including opsonization by complement and consequent phagocytosis. Several strains of GAS bind to human-specific complement inhibitors, C4b-binding protein (C4BP) and/or Factor H (FH), to curtail complement C3 (a critical opsonin) deposition. This results in diminished activation of phagocytes and clearance of GAS that may lead to the host being unable to limit the infection. Herein we describe the course of GAS infection in three human complement inhibitor transgenic (tg) mouse models that... (More)
Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is an important human bacterial pathogen that can cause invasive infections. Once it colonizes its exclusively human host, GAS needs to surmount numerous innate immune defense mechanisms, including opsonization by complement and consequent phagocytosis. Several strains of GAS bind to human-specific complement inhibitors, C4b-binding protein (C4BP) and/or Factor H (FH), to curtail complement C3 (a critical opsonin) deposition. This results in diminished activation of phagocytes and clearance of GAS that may lead to the host being unable to limit the infection. Herein we describe the course of GAS infection in three human complement inhibitor transgenic (tg) mouse models that examined each inhibitor (human C4BP or FH) alone, or the two inhibitors together (C4BPxFH or 'double' tg). GAS infection with strains that bound C4BP and FH resulted in enhanced mortality in each of the three transgenic mouse models compared to infection in wild type mice. In addition, GAS manifested increased virulence in C4BPxFH mice: higher organism burdens and greater elevations of pro-inflammatory cytokines and they died earlier than single transgenic or wt controls. The effects of hu-C4BP and hu-FH were specific for GAS strains that bound these inhibitors because strains that did not bind the inhibitors showed reduced virulence in the 'double' tg mice compared to strains that did bind; mortality was also similar in wild-type and C4BPxFH mice infected by non-binding GAS. Our findings emphasize the importance of binding of complement inhibitors to GAS that results in impaired opsonization and phagocytic killing, which translates to enhanced virulence in a humanized whole animal model. This novel hu-C4BPxFH tg model may prove invaluable in studies of GAS pathogenesis and for developing vaccines and therapeutics that rely on human complement activation for efficacy. (Less)
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author
organization
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type
Contribution to journal
publication status
published
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in
PLoS Pathogens
volume
11
issue
7
publisher
Public Library of Science
external identifiers
  • pmid:26200783
  • wos:000359365200049
  • scopus:84938785113
ISSN
1553-7366
DOI
10.1371/journal.ppat.1005043
language
English
LU publication?
yes
id
c0e84c59-90f4-44a4-b04d-f2f19a724af3 (old id 7714225)
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http://www.ncbi.nlm.nih.gov/pubmed/26200783?dopt=Abstract
date added to LUP
2015-08-10 21:19:04
date last changed
2017-10-01 03:28:31
@article{c0e84c59-90f4-44a4-b04d-f2f19a724af3,
  abstract     = {Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is an important human bacterial pathogen that can cause invasive infections. Once it colonizes its exclusively human host, GAS needs to surmount numerous innate immune defense mechanisms, including opsonization by complement and consequent phagocytosis. Several strains of GAS bind to human-specific complement inhibitors, C4b-binding protein (C4BP) and/or Factor H (FH), to curtail complement C3 (a critical opsonin) deposition. This results in diminished activation of phagocytes and clearance of GAS that may lead to the host being unable to limit the infection. Herein we describe the course of GAS infection in three human complement inhibitor transgenic (tg) mouse models that examined each inhibitor (human C4BP or FH) alone, or the two inhibitors together (C4BPxFH or 'double' tg). GAS infection with strains that bound C4BP and FH resulted in enhanced mortality in each of the three transgenic mouse models compared to infection in wild type mice. In addition, GAS manifested increased virulence in C4BPxFH mice: higher organism burdens and greater elevations of pro-inflammatory cytokines and they died earlier than single transgenic or wt controls. The effects of hu-C4BP and hu-FH were specific for GAS strains that bound these inhibitors because strains that did not bind the inhibitors showed reduced virulence in the 'double' tg mice compared to strains that did bind; mortality was also similar in wild-type and C4BPxFH mice infected by non-binding GAS. Our findings emphasize the importance of binding of complement inhibitors to GAS that results in impaired opsonization and phagocytic killing, which translates to enhanced virulence in a humanized whole animal model. This novel hu-C4BPxFH tg model may prove invaluable in studies of GAS pathogenesis and for developing vaccines and therapeutics that rely on human complement activation for efficacy.},
  articleno    = {e1005043},
  author       = {Ermert, David and Shaughnessy, Jutamas and Joeris, Thorsten and Kaplan, Jakub and Pang, Catherine J and Kurt-Jones, Evelyn A and Rice, Peter A and Ram, Sanjay and Blom, Anna},
  issn         = {1553-7366},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Pathogens},
  title        = {Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors.},
  url          = {http://dx.doi.org/10.1371/journal.ppat.1005043},
  volume       = {11},
  year         = {2015},
}