DNase Sda1 Allows Invasive M1T1 Group A Streptococcus to Prevent TLR9-Dependent Recognition

Satoshi Uchiyama, Federica Andreoni, Reto A. Schuepbach, Victor Nizet, Annelies S. Zinkernagel, PLoS Pathog. 2012 June 8(6): e1002736.

Speaker: Miao-Huei Cheng (鄭妙慧)                            Time:13:00~14:00, Feb. 27, 2013

Commentator: Dr. Chiou-Feng Lin (林秋烽老師)       Place: Room 601

Abstract

The Gram-positive bacterium group A Streptococcus (GAS) is an important human pathogen that can cause over 700 million cases of mild infections such as pharyngitis or pyoderma, and more than 650,000 cases of life-threatening invasive infections, including necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS) [1]. Recently studies indicate that severe GAS disease caused by a globally disseminated clone of the M1T1 serotype. Previous studies also showed that M1T1 strains are the most common cause of GAS pharyngitis and severe diseases such as NF and STSS. M1T1 GAS clone has an important virulence factor DNase Sda1. Sda1 can degrade DNA-based neutrophil extracellular traps and promote GAS to escape from phagocytic killing [2]. The Toll-like receptor 9 (TLR9) is located intracellularly and recognizes unmethylated CpG-rich DNA motifs which are usually present in microorganisms but not in the host genome [3]. Based on these concepts, the authors in this study show that only GAS DNA but not human DNA can induce macrophage secretion of proinflammatory cytokines including TNF-a and IFN-a. This secretion is dependent on the presence of functional TLR9. GAS uses Sda1 to degrade its own DNA fragments thus reduce TLR9-dependent cytokines release, which causes ineffective phagocytosis and contributes to bacterial survival. In a mouse necrotizing fasciitis model, the streptococcal DNase Sda1 also repressed TLR9-dependent TNF-a and IFN-a production. Overall, GAS can escape from innate immunity based on autodegradation of CpG-rich DNA by DNase Sda1.

References

1.          Carapetis JR, Steer AC, Mulholland EK, Weber M. (2005) The global burden of group A streptococcal diseases. Lancet Infect Dis 5: 685–694.

2.          Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK, et al. (2007) DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med 13: 981–985.

3.          Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745.