Investigating the metabolic and epigenetic basis of the immediate and persistent state of systemic immuneparesis following traumatic injury

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Owing to advancements in medical care, more victims of major trauma (e.g. road traffic accidents and stabbings) now reach hospital alive and survive life-saving operations. However, these survivors are at an increased risk of developing hospital-acquired infections (HAI), with >50% experiencing at least one infection during their hospital stay. The immediate clinical and economic impact of HAI are profound, with in-hospital mortality rates, length of hospital stay and inpatient costs all significantly higher in patients with HAI. Furthermore, survivors of HAI report poorer physical recovery, suffer from recurrent infections, require a greater degree of home care and are less likely to return to work. Thus, alongside the immediate and sustained health complications for patients, HAI place an increased economic burden on society.The immune system is the body's defence against infection, protecting us from harmful pathogens such as bacteria and fungi. Traumatic injury results in a significant reduction in the function of the immune system. This suppression, which occurs within minutes of the injury being sustained, is a major factor contributing to the increased susceptibility of trauma patients to HAI. However, despite this clinical impact, we currently know very little about the mechanisms that cause this decline in immune function and how quickly they occur. Identifying these mechanisms is crucial if new therapies for restoring immune function post-trauma are to be developed. Two processes are essential for immune cells to function. Firstly, they require energy, which they generate by a process called immunometabolism. Secondly, they must make and release molecules that alert the body to the presence of a pathogen. This step involves the immune cell making changes to the appearance of its DNA, and is termed epigenetics. When defects occur in either of these processes, immune cell function is reduced. Thus, could the immune suppression that develops post-trauma, and the high incidence of HAI amongst trauma patients, be explained by injury-induced changes in the processes of immunometabolism and epigenetics? To date, no study has investigated this question.Via a unique collaboration with critical-care paramedics, I work at the only UK research centre that has 24/7 access to blood samples obtained from trauma patients at the scene of their injury. These blood samples are acquired within 1-hour of injury, the so-called "Golden Hour", from patients that have sustained a traumatic brain injury (TBI) or an injury to their body. By analysing these samples, alongside blood samples that will be obtained from patients during their hospital stay (4-12 and 48-72 hours post-injury), on their day of hospital discharge, and 3 months post-injury, this project aims to examine the immediate and long-term impact of trauma on the processes of immunometabolism and epigenetics. I propose that trauma negatively effects both of these processes, resulting in impaired immune responses. To test this, I will compare the energy production and DNA profiles of immune cells isolated from trauma patients to those of healthy volunteers. Accompanying these studies will be experiments in an animal model of moderate TBI which also results in immune compromise. Providing me with samples of bone marrow, the site of immune cell production, this model will allow me to investigate whether any changes detected in the DNA profiles of circulating immune cells post-trauma originate during their formation in the bone marrow, or occur in the bloodstream post-injury. New therapies are urgently required for the treatment of HAI in trauma patients. To develop these, our understanding of injury-induced immune suppression must improve. By investigating how trauma impacts upon cellular processes that are critical for immune function, this project will yield new data that could assist in the development of novel therapies to prevent HAI post-trauma.