The activation of the oxidative stress response transcription factor SKN-1 in Caenorhabditis elegans by mitis group streptococci

The mitis group, a member of the genetically diverse viridans group streptococci, predominately colonizes the human oropharynx. This group has been shown to cause a wide range of infectious complications in humans, including bacteremia in patients with neutropenia, orbital cellulitis and infective endocarditis. Hydrogen peroxide (H(2)O(2)) has been identified as a virulence factor produced by this group of streptococci. More importantly, it has been shown that Streptococcus oralis and S. mitis induce epithelial cell and macrophage death via the production of H(2)O(2). Previously, H(2)O(2) mediated killing was observed in the nematode Caenorhabditis elegans in response to S. oralis and S. mitis. The genetically tractable model organism C. elegans is an excellent system to study mechanisms of pathogenicity and stress responses. Using this model, we observed rapid H(2)O(2) mediated killing of the worms by S. gordonii in addition to S. mitis and S. oralis. Furthermore, we observed colonization of the intestine of the worms when exposed to S. gordonii suggesting the involvement of an infection-like process. In response to the H(2)O(2) produced by the mitis group, we demonstrate the oxidative stress response is activated in the worms. The oxidative stress response transcription factor SKN-1 is required for the survival of the worms and provides protection against H(2)O(2) produced by S. gordonii. We show during infection, H(2)O(2) is required for the activation of SKN-1 and is mediated via the p38-MAPK pathway. The activation of the p38 signaling pathway in the presence of S. gordonii is not mediated by the endoplasmic reticulum (ER) transmembrane protein kinase IRE-1. However, IRE-1 is required for the survival of worms in response to S. gordonii. These finding suggests a parallel pathway senses H(2)O(2) produced by the mitis group and activates the phosphorylation of p38. Additionally, the unfolded protein response plays an important role during infection.