Authors

J Hewitson¹;  ¹ University of York, UK

Discussion

Joanna Greenman, Grace Boyd, Jack Fisher, Moses Egesa, Alison Elliott, David Kent, James Hewitson
People living in schistosome-endemic regions undergo repeated cycles of reinfection and drug clearance. To determine how chronic Schistosoma mansoni infection modifies responses to reinfection, we compared skin immune responses to S. mansoni challenge in mice that were chronically infected (12wks) with animals that were exposed for the first time. We found chronic infected leads to weak skin immune responses after rechallenge with marked reductions in macrophages, and that this is maintained after curative praziquantel treatment. As bone marrow (BM) chimera experiments revealed skin macrophages originate from infiltrating monocytes, we performed RNAseq on BM monocytes and found worm infection strongly impacts on gene expression in this site. We hypothesised distal worm infection impacts on bone marrow haematopoiesis by modifying the BM cytokine microenvironment. Cytokine Bead Array analysis showed chronic infection leads to elevated IL-4 (but not other type 2 cytokines) in BM aspirates. We next tested whether IL-4 can alter haematopoiesis and found haematopoietic stem cells (HSC) express Il4ra and in vitro assays (single cell cultures, colony formation assays) revealed HSC directly respond to this cytokine. Surprisingly then, the dominant signature of infection on immune progenitors (BM LSK cells) in vivo was instead interferon-related (type I and II). Using competitive bone marrow transplants, we found HSC from infected mice to be functionally impaired. We are now assessing the extent to which infection-induced changes to haematopoiesis persist after parasite clearance, and how this impacts on heterologous immune challenges in mice and humans.