Cell-free DNA epigenomics to track the dynamics of organ damage and immune exhaustion during sepsis

PROJECT SUMMARY
Sepsis is the most frequent cause of death in United States hospitals, and the number one cause of
death worldwide, responsible for 11 million deaths in 2017. Primary drivers of sepsis morbidity and
mortality are immune exhaustion leading to deadly secondary infection, and organ tissue damage
leading to multi-organ failure. Despite the critical importance of these processes in governing ultimate
sepsis outcomes, we have an incomplete understanding of their kinetics and dynamics. We thus
propose a two-pronged effort to shift our paradigm regarding sepsis dynamics through plasma cell-free
DNA analysis. Specifically, we propose to 1) track the dynamics of organ-specific damage, and 2) track
the dynamics of T cell exhaustion during sepsis. We will do this through analysis of daily blood samples
acquired from patients admitted to the intensive care unit for sepsis. Methodologically, we will achieve
these through genome-wide methylation sequencing of cell-free DNA. Bioinformatically, we will then
perform CIBERSORTx deconvolution to delineate and quantify specific cell/tissue types contributing to
plasma cell-free DNA, thus enabling us to infer organ tissues being damaged as well as T cell
exhaustion levels from both blood and tissue sources. The methods we will utilize here are highly
innovative yet feasible given recent literature and our own preliminary data. Our proposed work will
form the basis for a rich sepsis-focused research program utilizing cell-free DNA analysis to
answer major questions in the field with the potential to ultimately improve patient survival for
the deadliest disease worldwide.

Grant Number: 5R35GM142710-06
NIH Institute/Center: NIH
Principal Investigator: Aadel Chaudhuri