UMMS Affiliation

Division of Infectious Diseases and Immunology, Department of Medicine

Publication Date

7-22-2015

Document Type

Article

Disciplines

Bacterial Infections and Mycoses | Immunology of Infectious Disease | Immunopathology | Infectious Disease | Medical Immunology | Pathogenic Microbiology

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.

Rights and Permissions

Citation: PLoS Pathog. 2015 Jul 22;11(7):e1005043. doi: 10.1371/journal.ppat.1005043. eCollection 2015. Link to article on publisher's site

DOI of Published Version

10.1371/journal.ppat.1005043

Comments

Copyright: © 2015 Ermert 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

Related Resources

Link to Article in PubMed

Keywords

Bacterial pathogens, Complement activation, Complement inhibitors, Complement system, Cytokines, Genetically modified animals, Mouse models, Neutrophils

Journal/Book/Conference Title

PLoS pathogens

PubMed ID

26200783

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

 
 

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