dnase sda1 allows invasive m1t1 group a streptococcus to prevent tlr9-dependent recognitiondnase sda1允许外来m1t1 a群链球菌,防止tlr9-dependent认可.pdfVIP

DNase Sda1 Allows Invasive M1T1 Group A Streptococcus to Prevent TLR9-Dependent Recognition 1,2 1 2 3 1 Satoshi Uchiyama , Federica Andreoni , Reto A. Schuepbach , Victor Nizet , Annelies S. Zinkernagel * 1 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, 2 Division of Surgical Intensive Care, University Hospital Zurich, University of Zurich, Zurich, Switzerland, 3 Department of Pediatrics, Division of Pharmacology Drug Discovery and Skaggs School of Pharmacy Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America 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-a and TNF-a secretion from murine macrophages and contributed to bacterial survival. Similarly, in a murine necrotizing fasciitis model, IFN-a and TNF-a levels were significantly decreased in wild type mice infected with GAS expressing Sda1, whereas no such Sda1-dependent effect w