Temporal transcriptomic and epigenetic analysis of leukocytes in sepsis and COVID-19 patients

Sepsis is a life-threatening condition caused by the body's severe response to infection. Those who survive sepsis can develop long-term symptoms such as a persistent impairment of the immune system. This weakens the ability of sepsis survivors to fight infections and increases their risk of rehospitalization and death. Post-sepsis care is still poorly researched despite scientists predicting that rehospitalizations due to sepsis are increasing, especially with the COVID-19 pandemic. Sepsis is the most common life-threatening complication of COVID-19 and COVID-19 survivors can have similar long-term symptoms as sepsis survivors. It is not well understood why the immune system remains dysfunctional months after sepsis. To answer this question, we need to track how the immune system of a sepsis patient changes over time. My project will examine changes in gene expression (what genes turn on or off) in patients during and after sepsis, as well as in COVID-19 patients with sepsis, to determine what immune pathways are malfunctioning. At the same time, I will investigate changes in DNA methylation, which is an epigenetic process where methyl group molecules are added to areas of DNA to turn genes off for long periods of time. I hypothesize that DNA methylation is "locking in" the changes in gene expression to cause long-term immune dysfunction. I will then test if targeting the genes and pathways identified from these patient studies can prevent immune dysfunction in a cell model. The results from this project will identify the processes that cause long-term immune dysfunction, which is the first step for developing treatments that prevent sepsis survivors from falling sick again. Another potential outcome is the discovery of new biomarkers to diagnose sepsis patients earlier or predict patient survival. Overall, this project will help address a devastating but under-researched consequence of sepsis that affects many sepsis survivors.