Haematopoietic Stem Cell Transcriptome Rewiring Under Chronic Malaria Exposure: An Original Single-Cell Investigation of Malaria-Associated Bone Marrow Suppression in Nigerian Children

This dissertation conducts an original single-cell transcriptomic investigation of haematopoietic stem cell (HSC) transcriptome rewiring under conditions of chronic malaria exposure in Nigerian children, developing a mechanistic framework for understanding malaria-associated bone marrow suppression beyond erythrophagocytosis. Malaria-associated anaemia involves complex suppression of erythropoiesis that persists beyond parasite clearance and is not fully explained by immune-mediated red cell destruction alone. Bone marrow aspirates were collected from three groups at the University of Maiduguri Teaching Hospital: 40 children with severe malarial anaemia (SMA), 30 children with uncomplicated malaria, and 30 malaria-negative anaemic controls undergoing bone marrow evaluation for unrelated indications. Single-cell RNA sequencing (10x Chromium v3.1) was performed on 103,000 cells total. Trajectory analysis, regulon inference, and cell-cell communication modelling were applied. Pseudotime trajectory analysis demonstrated divergence of erythroid progenitor development at the basophilic erythroblast transition in SMA compared to uncomplicated malaria, with an aberrant inflammatory erythroid progenitor subpopulation identified only in SMA (15.3 percent of erythroid compartment). This novel erythroid subpopulation showed high expression of IFN-gamma-induced STAT1-target genes and low GATA1 target expression, proposing an interferon-mediated erythropoietic block as the primary molecular event. HSC self-renewal transcription factor networks were persistently suppressed in SMA. An original Malaria-HSC Suppression Model integrating the inflammatory erythroid progenitor biology is proposed with implications for anaemia management in high-transmission settings. Keywords: haematopoietic stem cells, malaria-associated anaemia, single-cell transcriptomics, bone marrow suppression, Nigeria.