Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors

PLoS Pathogens

Catherine J. Pang¹  Sanjay Ram²  Jutamas Shaughnessy²  Anna M. Blom²  Peter A. Rice²  Thorsten Joeris²  David Ermert³  Evelyn A. Kurt-Jones³  Jakub Kaplan⁴ 

[1] Department of Experimental Medical Science, Immunology section, Lund University, Lund, Sweden;Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden;Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg C, Denmark

关键词: Mouse models;    Complement inhibitors;    Cytokines;    Complement system;    Neutrophils;    Phagocytosis;    Animal models of infection;    Genetically modified animals;   

DOI  :  10.1371/journal.ppat.1005043

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY