Abstract
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 (H2O2) 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 H2O2. Previously, H2O2 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 H2O2 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 H2O2 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 H2O2 produced by S. gordonii. We show during infection, H2O2 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 H2O2 produced by the mitis group and activates the phosphorylation of p38. Additionally, the unfolded protein response plays an important role during infection.
Highlights
A previous study by Bolm, et al established that S. oralis and S. mitis caused the death of the worms via the production of H2O2 in liquid killing assays [20]
In addition to these strains, we compared the survival of worms on S. gordonii, S. mutans, and S. salivarius grown on Todd Hewitt agar supplement with yeast extract relative to non-pathogenic E. coli OP50
The production of H2O2 is mainly attributed to the pyruvate oxidase SpxB enzyme activity, which is conserved among the mitis group streptococci [35]
Summary
Members of the mitis group of streptococci, which are part of the viridans group of streptococci (VGS), are commensals of the oral cavity and the upper respiratory tract of humans. Pneumococcal H2O2 induced the activation of stress related cellular signaling pathways confirming the role of H2O2 as an important virulence factor of the mitis group [17]. Phase II reactions provide protection against Reactive Oxygen Species (ROS)-induced oxidative stress damage in tissues that are associated with many diseases and aging [23, 24]. Oxidative stress induced activation is facilitated by the phosphorylation of SKN1 via the p38 MAPK pathway [31]. ROS produced by the dual oxidase Ce-DUOX-1/BLI-3 in response to pathogens activates SKN-1 through the p38 MAPK pathway [32]. Based on our data the activation of p38 MAPK pathway does not require IRE-1 as previously seen during oxidative stress induced by arsenite. In the presence of S. gordonii phosphorylation of PMK-1 is not dependent on Ce-Duox1/BLI-3
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