Investigating cholesterol biosynthesis gene expression in immune cell transcriptomes during sepsis and human endotoxemia

Abstract

Sepsis is a complex illness caused by an inappropriate host response to infection that results in acute, life-threatening organ dysfunction. In 2017, the global incidence of sepsis was estimated to be 48.9 million cases, with 11 million sepsis-related deaths representing 19.7% of all deaths worldwide. Sepsis can affect people of all ages; however, it is more common among the elderly. In particular, as people get older, they become more susceptible to pneumonia, which is a primary cause of sepsis. Recent studies have identified a cholesterol biosynthesis pathway in relation to the phenomenon of immune tolerance in circulating monocytes of hospitalized patients with community-acquired pneumonia (CAP). Whether the cholesterol biosynthesis pathway is activated in the context of critical illness due to sepsis secondary to CAP, as well as acute systemic inflammation, is not well-defined. Therefore, the study hypothesis is that sepsis secondary to CAP is associated with cholesterol biosynthesis gene signatures. To test this hypothesis, publicly available genome-wide gene expression data from sepsis patients diagnosed with CAP on intensive care unit admission will be used to investigate a cholesterol biosynthesis signature using bioinformatics tools. In addition, publicly available data from healthy participants in a human endotoxemia study will be utilized to test the association of the cholesterol biosynthesis signature with different time points after endotoxin exposure. In order to validate findings from genome-wide analyses, the inducibility of genes involved in the cholesterol biosynthesis pathway will be tested in an in vitro model of human monocyte tolerance.