Understanding the long-term haematological consequences of infection exposure

Infectious disease remains a global health burden. Blood and immune cells play a central role in underlying pathology, however long-term consequences of infection on these cells in otherwise healthy people are unknown. This project aims to understand whether infection modifies cellular programmes, leaving scars on the haematopoietic system, even after recovery, that compromise health in later life. Using a murine influenza model, non-infected, infected and recovered groups (where subjects are administered antiviral treatment post-infection and are analysed after a period of time) will be investigated. By combining a DNA barcoding tool with single cell Multiome analysis of bone marrow cells from these groups, a high dimensional comparison of the transcriptome and epigenome of sister cells will be generated. These data will address fundamental questions including whether cell fate potential is and remains perturbed by infection. Next, following bioinformatic stratification of the data and employing in vitro functional experiments to screen candidate genes using CRISPR-Cas9, molecular targets to be manipulated in vivo will be identified. These experiments will address whether it is possible to mitigate effects of infectious perturbations on the haematopoietic system. Overall, this work will begin to elucidate mechanisms driving the response to infection and highlight potential therapeutic interventions.