Single cell metabolic profiling of T-cells in sepsis to identify mechanisms of immune suppression – a pilot study

Summary

Sepsis refers to life-threatening organ dysfunction due to infection. Sepsis is extremely common and accounts for a significant proportion of critical care admissions. Importantly, these patients have a high risk of dying (1 in 3) that has not reduced significantly in recent decades. Treatment remains supportive (e.g. antibiotics, fluids), with no new treatments shown to save lives consistently.

Sepsis is associated with striking abnormalities of the immune system (a system that fights infection) but it is unclear which are most important.
Critically ill patients with sepsis are more susceptible to other infections with organisms that would not usually cause disease. This is indicative of immune suppression, particularly suppression of immune cells called T-cells which normally kill invading organisms.

Correct T-cell function is dependent on their correct use of nutrients to produce energy (metabolism). Defective metabolism results in abnormal function, which is potentially treatable.

We plan to use novel laboratory techniques to study the metabolism and function of T-cells in sepsis. We will measure the expression of critical proteins (enzymes) in metabolic pathways that allow T-cells to fight infection. We will compare patients who survive (good outcome) to those who do not (poor outcome) to see if T-cell metabolism might help explain the difference.

This proof-of-concept work will characterise metabolic alterations and immune dysfunction in sepsis and identify which pathways might yield novel drug targets. Given the clinical overlap between sepsis and other forms of critical illness, it is likely that these results would have broader implications for other diseases.