Defining how critical illness-induced dysregulated monopoiesis affects long-term immunity in ICU survivors to inform therapeutic strategies

Improvements in treatment of critically-unwell patients have led to increased survival. However, once discharged from hospital, the morbidity and mortality of these survivors remains high relative to their peers in the general population. This has been attributed in part, to a persistent dysregulated immune function, underscored by the fact that infection remains the commonest cause for hospital readmission in cohorts of Intensive Care Unit (ICU)-survivors. I have previously demonstrated that Acute Respiratory Distress Syndrome (ARDS)-associated hypoxia alters immune responses in the bone-marrow (BM), hindering and shaping emergency monopoiesis. I now show that this phenotype is not restricted to ARDS, but it can in fact, be found in other critical illnesses, including trauma. I therefore propose that critical illness-induced effects in the BM niche induces dysregulated monopoiesis, that in turn, shapes the function of the monocyte-derived cells in their terminal organs with long-term immune consequences. This program of work aims to understand the mechanisms governing critical illness-induced dysregulated emergency monopoiesis, investigate the long-term immune consequences of the resultant monocyte-derived cells within tissues and finally, develop therapeutic approaches to alter these dysregulated phenotypes with a view of improving long-term outcomes for these patients.