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.
Highlights
Streptococcus pyogenes, known as Group A Streptococcus (GAS) is an important human bacterial pathogen that is widespread and responsible for more than 700 million infections globally each year [1]
Streptococcus pyogenes is an important cause of human infections worldwide, ranging from mild and superficial disease to life-threatening invasive infections
Because S. pyogenes bind only human, but not mouse complement inhibitors, we used novel strains of humanized mice that produce two human complement inhibitory proteins which allowed us to analyze the impact of human-specific human complement inhibition on the severity of S. pyogenes infections in mice
Summary
Streptococcus pyogenes, known as Group A Streptococcus (GAS) is an important human bacterial pathogen that is widespread and responsible for more than 700 million infections globally each year [1]. GAS causes a spectrum of diseases, ranging from milder pharyngitis and superficial skin infections to more severe illnesses that include acute rheumatic fever (that may be complicated by rheumatic heart disease), post-streptococcal glomerulonephritis and invasive infections. The latter may be accompanied by life-threatening sepsis, streptococcal toxic shock syndrome and/or necrotizing fasciitis [2, 3]. A key first line of defense against bacterial pathogens involves the complement system, which comprises over 30 soluble proteins and several membrane-associated complement receptors and inhibitors. Gram-positive bacteria such as GAS are resistant to MACmediated lysis, but are eliminated by phagocytes following opsonization with C3b and iC3b. The complement cascade is tightly regulated by surface bound and soluble inhibitors (or regulators); C4b-binding protein (C4BP) and Factor H (FH) are two examples of the latter which serve to prevent damage to host tissues
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