Balancing Endothelial Training and Tolerance: Innate Immune Memory in Malaria Pathogenesis

Malaria, predominantly caused by Plasmodium falciparum, remains a major global health challenge. While research has traditionally focused on adaptive immunity, emerging evidence highlights a critical role for innate immune memory in disease progression—particularly involving endothelial cells (ECs). Situated at the blood–tissue interface, ECs are not passive barriers but active participants in immune regulation, capable of developing memory-like responses through epigenetic and metabolic reprogramming. This review examines how repeated or chronic malaria exposure shapes EC behavior via trained immunity (a heightened, pro-inflammatory state) or trained tolerance (a hyporesponsive, anti-inflammatory state). Acute infections promote EC activation through pathogen recognition and cytokine signaling, whereas chronic or repeated infections induce tolerogenic adaptations that preserve vascular integrity and limit immunopathology. Malaria-derived molecules, such as hemozoin, glycosylphosphatidylinositols, and extracellular vesicles—modulate these memory states alongside cytokine cues like IL-1β and TGF-β. Despite growing recognition of EC plasticity, major gaps remain, particularly regarding the molecular distinction between trained and tolerized ECs, tissue-specific responses in organs like the brain and placenta, and the durability of memory states. The interplay of endothelial memory with malaria severity and tolerance has yet to be fully explored in human settings. Future research integrating single-cell profiling, spatial mapping, and clinical data is needed to clarify the immunoregulatory functions of ECs in malaria and assess their potential as therapeutic targets. This review highlights the importance of endothelial immune memory in shaping host–pathogen dynamics and underscores its relevance for understanding disease tolerance in malaria-endemic populations. Key words: Endothelial Cells, Trained Immunity, Trained Tolerance, Innate Immune Memory