Selective Advantages of Invasive Emm1 Type Group a Streptococcus under Acidic Stress

Group A Streptococcus (GAS) is an important human pathogen, causing diseases including pharyngitis, scarlet fever, cellulitis, necrotizing fasciitis, toxic shock syndrome, and rheumatic heart diseases. Mortality rate of invasive GAS infections is up to 30% to 70%; however, no vaccine or effective prevention strategies have been developed to against GAS infection. CovR/CovS (CovR/S) is a two-component regulatory system that acts primarily to repress target genes expression. Sensor kinase CovS responds to Mg++, antimicrobial peptide LL37, and was considered to be required for GAS survival under mild stress conditions including low pH, elevated temperature, and high osmolarity. However, clinical studies showed that prevalent emm1 type isolates with mutation in covS gene are highly correlated with invasive severe diseases, suggesting that the loss of CovS increases bacterial virulence and fitness during infection. Activation of phagocytic cells, increasing of oxidative stress, and decreasing of tissue pH are general stresses constitute the primary defense in inflammatory site against bacterial infection. Our preliminary results showed that the growth activity of the emm1 covS mutant under oxidative stress, or in neutral and acidic conditions, is similar. However, the de-repression of a specific group of virulence genes expression under acidic conditions was only found in the covS mutant but not in the wild-type strain. These results suggest that the mutation in covS may be a critical process for GAS to inactivate CovR and derepress of virulence genes expression under acidic stress. Mutations in covS of GAS is highly associated with invasive diseases, to clarify whether the transcriptome changes in the covS mutant under acidic stress will provide selective advantages for GAS during infections, and whether acidic stress is the major driven force of selection of mutations in CovR/S system, may provide new strategies to prevent or treat invasive GAS infections. Acidic stress of phagosome is the primary defense against GAS infection. It has been known that resistance of phagocytic clearance is one of the most important steps for GAS to establish successful infections. In the present proposal, roles of intracellular acidic stress on selection of mutations in CovR/S system will be analyzed by U937 cell infection model. In addition, the contribution of covS mutation on GAS pathogenesis and transcriptome changes under acidic conditions will be studied by utilizing newly developed technologies such as Phos-tag and RNA-seq. Results from this proposal will help us to further understanding the interaction between GAS and host during infections, and the importance of covS mutation in GAS pathogenesis.

Project ID:PC10501-1546
External Project ID:MOST103-2320-B182-025-MY3