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

Abstract

Group A Streptococcus (GAS) has developed a broad arsenal of virulence factors that serve to circumvent host defense mechanisms. The virulence factor DNase Sda1 of the hyperinvasive M1T1 GAS clone degrades DNA-based neutrophil extracellular traps allowing GAS to escape extracellular killing. TLR9 is activated by unmethylated CpG-rich bacterial DNA and enhances innate immune resistance. We hypothesized that Sda1 degradation of bacterial DNA could alter TLR9-mediated recognition of GAS by host innate immune cells. We tested this hypothesis using a dual approach: loss and gain of function of DNase in isogenic GAS strains and presence and absence of TLR9 in the host. Either DNA degradation by Sda1 or host deficiency of TLR9 prevented GAS induced IFN-α and TNF-α secretion from murine macrophages and contributed to bacterial survival. Similarly, in a murine necrotizing fasciitis model, IFN-α and TNF-α levels were significantly decreased in wild type mice infected with GAS expressing Sda1, whereas no such Sda1-dependent effect was seen in a TLR9-deficient background. Thus GAS Sda1 suppressed both the TLR9-mediated innate immune response and macrophage bactericidal activity. Our results demonstrate a novel mechanism of bacterial innate immune evasion based on autodegradation of CpG-rich DNA by a bacterial DNase.

IgA Enhances NETosis and Release of Neutrophil Extracellular Traps by Polymorphonuclear Cells via Fcα Receptor I

“…Bacterial strains that express DNase as virulence factor were shown to break down NETs and disseminate more efficiently (28)(29)(30). Furthermore, it was recently shown that NETs, which are formed in the vasculature, efficiently trapped bacteria in the bloodstream, and in vivo removal of NETs by administration of recombinant DNase promoted hypersusceptibility to sepsis (31)(32)(33).…”

“…Several groups have demonstrated that formation of NETs impaired bacterial survival (14,30,(38)(39)(40). However, others showed entrapment of bacteria or Candida albicans by NETs without killing (41).…”

Carriage of Streptococcus pyogenes in Primary School Children: M-Protein Types, Pyrogenic Toxin Genes, and Investigation of the Clonal Relationships Between the Isolates

“…Bu araştırmanın sonucunda, klinik görü-nüm ile emm tipleri veya virülans faktörleri arasında bir korelasyon olmadığı, buna karşın konak immün yanıtının belirleyici olduğu vurgulanmıştır 28 . Uchiyama ve arkadaşları 29 ise, GAS ile ilişkili farklı virülans faktörlerini ve bunların immün sistemle olan ilişkilerini araş-tırmışlardır. Bu çalışmada, yakın zamanda keşfedilen bir diğer GAS virülans faktörü olan streptodornaz (Sda1)'ın, doğal immün yanıtın bir parçası olan Toll benzeri reseptör-9 (TLR-9) üzerine olan etkisini tespit etmek için, deneysel hayvan modeli oluşturulmuştur.…”

“…Bu çalışmada, yakın zamanda keşfedilen bir diğer GAS virülans faktörü olan streptodornaz (Sda1)'ın, doğal immün yanıtın bir parçası olan Toll benzeri reseptör-9 (TLR-9) üzerine olan etkisini tespit etmek için, deneysel hayvan modeli oluşturulmuştur. Sonuç olarak, Sda1'in TLR-9 aracılı immün yanıtı baskıladığı ve bu sayede GAS'ın, makrofajların bakterisidal etkilerinden kaçabildiği belirlenmiştir 29 . Ne var ki, bütün bu araştır-malara karşın, GAS'a karşı gelişen immün yanıtın bireyler arasında neden bu kadar farklı olduğu net olarak cevaplanamamıştır.…”

Contribution of nuclease to the pathogenesis of Aeromonas hydrophila

“…13 ETs are also likely to alert the immune system by activating DNA receptors, such as TLR-9, which aid in immune cell recruitment and the mounting of an acquired immune response or in reducing inflammation. 32 Successful microbial pathogens have in turn evolved complex and efficient methods to overcome immune mechanisms. Multiple virulence factors that counteract ETs have been identified.…”