Scl1‐dependent internalization of group A Streptococcus via direct interactions with the α2β1 integrin enhances pathogen survival and re‐emergence

The molecular pathogenesis of infections caused by group A Streptococcus (GAS) is not fully understood. We recently reported that a recombinant protein derived from the collagen-like surface protein, Sel1, bound to the human collagen receptor, integrin α 2 β 1 . Here, we investigate whether the same Sel1 variant expressed by GAS cells interacts with the integrin α 2 β 1 and affects the biological outcome of host-pathogen interactions. We demonstrate that GAS adherence and internalization involve direct interactions between surface expressed Sel1 and the α 2 β 1 integrin, because (i) both adherence and internalization of the scl1-inactivated mutant were significantly decreased, and were restored by in-trans complementation of Sel1 expression, (ii) GAS internalization was reduced by pre-treatment of HEp-2 cells with anti-α 2 integrin-subunit antibody and type I collagen, (iii) recombinant α 2 -l domain bound the wild-type GAS cells and (iv) internalization of wild-type cells was significantly increased in C2C12 cells expressing the α 2 β 1 integrin as the only collagen-binding integrin. Next, we determined that internalized GAS re-emerges from epithelial cells into the extracellular environment. Taken together, our data describe a new molecular mechanism used by GAS involving the direct interaction between Sel1 and integrins, which increases the overall capability of the pathogen to survive and re-emerge.