Project Summary How can we promote health and survival during infection? Clinically, most patients are treated with drugs that work to eliminate the pathogen: antibiotics, antivirals, antifungals, etc., but this approach is often insufficient. The primary determinant of survival during infection is the host’s ability to prevent, withstand, or repair damage. Thus, eliminating the pathogen is not necessarily sufficient for survival. This is particularly relevant during sepsis, an infection in which the host response causes much more damage than the microbe itself. To address this disconnect, over the past decade the Ayres lab has pioneered cooperative defenses, a new infection defense framework focused on promoting health independent of pathogen burden. Cooperative defenses include anti-virulence strategies which neutralize pathogen- or host-derived virulence signals before they cause damage in the host (e.g. preventing maladaptive cytokine production) and disease tolerance strategies which prevent physiological damage in the presence of virulence signals (e.g. metabolic shifts that prevent damage from excess cytokine production). The Ayres lab has established a novel approach to identifying cooperative defense mechanisms by leveraging the decades-old phenomenon of the lethal dose 50 (LD50). LD50 is the dose of a pathogen that kills 50% of a genetically identical host population while the other 50% survives. Strikingly, for many infections, surviving and dying LD50-infected mice exhibit the same pathogen burden throughout the course of the infection, indicating that LD50-infected surviving mice survive due to differences in their ability to engage cooperative defenses. An LD50 polymicrobial bacterial sepsis model has identified serotonin neutralization as a candidate cooperative defense mechanism during sepsis. Preliminary data demonstrates inhibiting peripheral serotonin during polymicrobial sepsis promotes health and survival through cooperative defense mechanisms. While serotonin is most commonly studied in its role as a neurotransmitter, 95% of the body’s serotonin is found in the periphery, largely carried by platelets in circulation. Recent research has begun to elucidate the role of this peripheral serotonin in regulating a wide variety of processes: chief among these are inflammation and metabolism. Widespread platelet activation occurs during sepsis, inducing platelet serotonin release, yet the effects of this serotonin and the means by which it is handled are not well understood. Three specific aims will be addressed: 1) Determine the impact of serotonin on cooperative defenses during sepsis, 2) Determine how inhibition of serotonin signaling promotes health and survival during polymicrobial sepsis, and 3) Determine the mechanisms by which serotonin is neutralized during a cooperative defense response to sepsis. This research will take place at the Salk Institute for Biological Studies. In addition to these research objectives, the propos...