Grant: Discovery Grants Program - Individual

Fever is a common consequence of infection. In response to proinflammatory signals that follow pathogen recognition, the brain's hypothalamus turns up the thermostat and we experience the classical increase in body temperature. This biological response has been conserved for 550 million years of evolution, arguing that it must serve a beneficial purpose. Yet, most of us automatically reach for antipyretic drugs to inhibit it. But is this prolonging disease? Exciting new results from my lab demonstrate that moderate fever helps to clear infections through accelerated (not stronger) activation of immune defences, and that this is followed by efficient control of inflammation and repair of damaged tissue. This integration offers one of the strongest arguments for the evolutionary conservation of fever. Importantly, through this work we also identified new functionality in the fish immune system. In short, fish take advantage of their environment to induce and control fever, modulate immunity and, ultimately, improve their health and performance through a natural drug-free biological response. This presents a tremendous opportunity when we are in dire need of solutions to global food and nutrition security, we need to take pressure off from an over-fished ocean, and must do better at helping to restore wild fish stocks. However, key fundamental biological questions must be answered before we can apply this knowledge. Herein, I propose to use a combined molecular and cell biology approach that employs fish infection models and cell culture techniques to test three complementary but non-overlapping hypotheses: Hypothesis 1: Fever promotes cellular and molecular immune responses that are tailored to different pathogens. Hypothesis 2: Fever decreases host susceptibility to secondary infections. Hypothesis 3: Fever-associated sickness behaviours decrease the incidence of infectious disease transmission. Nearly all fish infection models, techniques, reagents, and infrastructure are already in place in my lab. Remaining items are supported by university facilities and collaborators. The proposed research will offer new opportunities for experimental design (breadth and depth) and enrich the training ground for an enthusiastic diverse team of trainees that continue to thrive and develop highly marketable skills in a challenging, equitable, inclusive, and collaborative lab environment. Our work will: 1) provide important evolutionary context for the contributions of fever to health and disease, 2) help to crystallize a natural strategy that will increase the resilience of the aquaculture sector and fish being raised for wild population restoration projects, and 3) offer a novel avenue to help address twin challenges of global food security and environmental sustainability, with regional considerations designed to positively impact the marginalized communities that are most at risk and should serve as active partners in these solutions.