Biological drivers of the host response in sepsis

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection. Immune dysregulation arises from responses that initially were activated to protect against pathogens and preserve tissue integrity. Disturbed resistance mechanisms can result in excessive inflammation alongside immunosuppression, each of which is considered important biological drivers of the immunopathology of sepsis. Key inflammatory drivers are excessive proinflammatory cytokine activity, complement and coagulation system activation and endothelial dysfunction. Conversely, sepsis-induced immunosuppression is marked by lymphocyte exhaustion, reduced monocyte human leucocyte antigen-DR expression, and the emergence of myeloid-derived suppressor cells. Within this complex immunological environment, the gut microbiome influences host immunity through the release of short-chain fatty acids and bacterial metabolites. Thus far, immunomodulatory trials in patients with sepsis paid little attention to the identification of dominant biological drivers, which might enrich the population for those who are more likely to respond to a certain intervention. Recently, retrospective analyses of such trials, as well as small prospective trials, have provided proof of concept that subgroups of sepsis patients can be identified with specific immunological profiles, either based on a single biomarker or on high-dimensional data, that respond differently to immunomodulation. This review explores the biological drivers of sepsis immunopathology, highlighting the challenges in translating preclinical insights into effective therapies and the potential of personalised medicine approaches to improve sepsis outcomes.