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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., Author Summary To fight infection, an animal's immune response produces a variety of toxic compounds that are directed at the invading pathogen. However, these toxic compounds can also damage the host's tissue. Therefore 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. Upon exposure of C. elegans to reactive compounds, a factor called SKN-1 was shown to induce the production of protective, detoxifying enzymes. Here, we demonstrate that SKN-1 also becomes active in infected animals. The cause of SKN-1 activation is reactive compounds produced by the animal's immune system, i.e. a source of “friendly fire.” We additionally show that a highly conserved signaling pathway, called the p38 MAPK pathway, controls SKN-1 activity during infection. Finally, we demonstrate that SKN-1 activity is beneficial to the worm during infection, enhancing survival. Because humans share many of the components of the interaction we describe, this study provides broad insights into the principals of damage control during immune response.