Grant: Project Grant

With the widespread availability of antibiotics to kill bacteria, and of intensive care units (ICUs) to support patients with otherwise life-threatening vital organ failure, the major threat to survival for critically ill patients is the adverse effects of the immune response to infection; this deleterious host defense process is called sepsis. Circulating white blood cells called neutrophils (PMNs) play a key role in both the initial response to infection and in the lethal organ injury that results from that response. PMN activity - both beneficial and detrimental - is critically impacted by the capacity of the PMN to undergo cellular suicide through a process called apoptosis. My laboratory has found that the ability of the PMN to undergo apoptosis is regulated by subtle and inducible changes in caspase-8, the enzyme responsible for initiating apoptosis. The simple addition of a phosphate molecule to caspase-8 transforms its function from pro-to anti-apoptotic, and results in the activation of pro-survival and pro-inflammatory mechanisms in the PMN. Our work seeks to understand how this process, known as phosphorylation, is regulated, and how it might be targeted to improve the survival of patients with sepsis. We will first determine the role played by caspase-8 phosphorylation in the initial response of PMN to bacteria and their products. We will then study the mechanisms that support or block the phosphorylation of caspase-8. Finally we will determine how these changes impact key elements of PMN function. Our studies will use PMN from critically ill septic patients to understand mechanisms, and experimental models in zebrafish and mice to study the consequences of modifying the caspase-8 phosphorylation state. In aggregate they will both shed light on a novel mechanism involved in the regulation of inflammation, and provide a rational basis for treatments for sepsis based on accelerating the resolution of inflammation.