Investigation of immune pathways and genetics underlying resistance and tolerance in severe infection

Infection is very common, but rarely deadly. For my PhD I want to explore the balance between 'resistance' to infection - the ability to kill and destroy invading pathogens like bacteria, fungi and viruses, with 'tolerance' to infection - the ability to bear an infection without adverse effects when these pathogens attack. Both these strategies are governed by immune pathways and are critical to survival from infection. I will focus on whether we can use large human studies, model or in vitro work about the activity of genes when we do get infected and attempt to identify specific pathways that are a 'trade-off' between these two evolutionary strategies - tolerance and resistance . I will target my investigation on the haem degradation pathway, which controls iron transport and storage. Iron is a critical nutrient for both hosts and pathogens, and has been shown to be important in determining infection outcomes. I will explore how this pathway is regulated in large datasets from sepsis and COVID-19 patients. I will also explore the balance between incidence and case fatality of infection using large genetic datasets, to explore whether genes that make you resist infection are more likely to make you die.