Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors

        David Ermert, Jutamas Shaughnessy, Thorsten Joeris, Jakub Kaplan, Catherine J. Pang, Evelyn A. Kurt-Jones, Peter A. Rice, Sanjay Ram, Anna M. Blom

Plos Pathogen, 11: e1005043. July 22, 2015

Speaker: Meng-Ju Tsai (蔡孟儒)                                                  Time: 15:00~16:00, Oct. 07, 2015

Commentator: Dr. Pei-Jan Tsai (蔡佩珍老師)                    Place: Room 601

Abstract:

  Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is an important human bacterial pathogen that can cause a spectrum of disease, ranging from milder pharyngitis to severer invasive infection. To overcome innate immune defense mechanism, including opsonization by complement and consequent phagocytosis, GAS produces several virulence factors that interact with human proteins. Among them are the M protein family members which interact with human C4b binding protein (C4BP) and human Factor H (FH), and curtail complement C3 deposition on bacterial surface to diminish activation of phagocytes [1, 2]. However, several GAS strains do not bind mouse complement inhibitors and, therefore, the wild type mouse models are not suitable for these strains and the in vivo evidence has been lacking. To solve this problem, the authors generated three transgenic mouse models which expressed either human C4BP or human FH, or both complement inibitors (C4BPxFH). Compared to the wild type mouse, these three transgenic mice showed higher mortality, with the C4BPxFH mouse showing highest mortality, after infection by AP1, a strain that produces M protein and another M protein family member, protein H. Further, a mutant deficient in both the M protein and protein H showed reduced virulence in the C4BPxFH mouse. These results suggest that the bound C4BP and FH might enhanced the virulence of AP1 in the transgenic mice. The AP1-infected C4BPxFH mice had higher organism burdens and exhibited greater elevations of pro-inflammatory cytokines and this may explain why they died earlier than the wild type mouse. Consistently, the strains of GAS whose M protein did not bind the inhibitors showed similar mortality in the wild type and C4BPxFH mice. Taken together, the binding of C4BP and FH is important for GAS to impair opsonization and evade phagoctosis. These mouse models may prove invaluable in studies of GAS pathogenesis and also for developing therapeutics.

References:

1.         Thern A, Stenberg L, Dahlback B, Lindahl G (1995). Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system. J Immunol. 154:375–386.

2.         Horstmann RD, Sievertsen HJ, Knobloch J, Fischetti VA. (1988). Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H. Proc Natl Acad Sci U S A. 85:1657–1661.