Abstract
Infected animals will produce reactive oxygen species (ROS) and other inflammatory molecules that help fight pathogens, but can inadvertently damage host tissue. Therefore specific responses, which protect and repair against the collateral damage caused by the immune response, are critical for successfully surviving pathogen attack. We previously demonstrated that ROS are generated during infection in the model host Caenorhabditis elegans by the dual oxidase Ce-Duox1/BLI-3. Herein, an important connection between ROS generation by Ce-Duox1/BLI-3 and upregulation of a protective transcriptional response by SKN-1 is established in the context of infection. SKN-1 is an ortholog of the mammalian Nrf transcription factors and has previously been documented to promote survival, following oxidative stress, by upregulating genes involved in the detoxification of ROS and other reactive compounds. Using qRT-PCR, transcriptional reporter fusions, and a translational fusion, SKN-1 is shown to become highly active in the C. elegans intestine upon exposure to the human bacterial pathogens, Enterococcus faecalis and Pseudomonas aeruginosa. Activation is dependent on the overall pathogenicity of the bacterium, demonstrated by a weakened response observed in attenuated mutants of these pathogens. Previous work demonstrated a role for p38 MAPK signaling both in pathogen resistance and in activating SKN-1 upon exposure to chemically induced oxidative stress. We show that NSY-1, SEK-1 and PMK-1 are also required for SKN-1 activity during infection. Evidence is also presented that the ROS produced by Ce-Duox1/BLI-3 is the source of SKN-1 activation via p38 MAPK signaling during infection. Finally, for the first time, SKN-1 activity is shown to be protective during infection; loss of skn-1 decreases resistance, whereas increasing SKN-1 activity augments resistance to pathogen. Overall, a model is presented in which ROS generation by Ce-Duox1/BLI-3 activates a protective SKN-1 response via p38 MAPK signaling.
Highlights
Infection by pathogenic microorganisms requires a coordinated response from the host to cope with the multitude of physiological challenges presented by the attack
An important job of the immune response is to prevent and repair damage caused by ‘‘friendly fire.’’ In this study, we explore this damage control function of the immune response in a small worm called C. elegans, which can be infected by feeding on human pathogens and serves as a model of human infection
The cause of SKN-1 activation is reactive compounds produced by the animal’s immune system, i.e. a source of ‘‘friendly fire.’’ We show that a highly conserved signaling pathway, called the p38 MAPK pathway, controls SKN-1 activity during infection
Summary
Infection by pathogenic microorganisms requires a coordinated response from the host to cope with the multitude of physiological challenges presented by the attack. In this work we explore the connections between infection, immune response and cellular stress response using the wellstudied model host Caenorhabditis elegans. The best-studied example is the production of ROS as an antimicrobial response in the phagolysosome of phagocytic cells by the NADPH oxidase gp91phox. This response is not limited to phagocytes, and NADPH oxidases are present in the skin as well as the mucosal epithelium of the oral cavity, respiratory and gastrointestinal tracts of humans [1,2]. The goal of this work was to determine if infection, by triggering ROS release by Ce-Duox1/ BLI-3, induces an oxidative stress response in the host as part of the overall response to the pathogen
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