Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection
Authors listMyriam LR Haltalli Samuel Watcham Nicola K Wilson Kira Eilers Alexander Lipien Heather Ang Flora Birch Sara Gonzalez Anton Chiara Pirillo Nicola Ruivo Maria L Vainieri Constandina Pospori Robert E Sinden Tiago C Luis Jean Langhorne Ken R Duffy Berthold Göttgens Andrew M Blagborough Cristina Lo Celso
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and-coupled with reactive oxygen species quenching-enables partial rescuing of HSC function.
Journal Nature Cell Biology
Issue number 12