title: Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors.
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.
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden; Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Ermert
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jutamas
authors.initials: J
authors.lastname: Shaughnessy
authors.affiliation: Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg C, Denmark; Department of Experimental Medical Science, Immunology section, Lund University, Lund, Sweden.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Joeris
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Pang
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D003167:Complement Activation; D051056:Complement Inactivating Agents / Q000276:immunology*; D006801:Humans; D051379:Mice; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D051056:Complement Inactivating Agents