Cerebral Malaria as an Autoimmune-like Disease Driven by Pathogenic B cell Responses and Systemic Inflammation
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Cerebral malaria (CM) is a life-threatening complication of Plasmodium infection, traditionally attributed to parasite sequestration and inflammation. Here, we identify the spleen as a central driver of systemic lethal inflammation, with B cell-mediated humoral immunity playing a key role in disease progression. Single-cell sequencing reveals that GLUT1⁺ marginal zone macrophages (MZMs) activate B cells and promote autoantibody production, amplifying immunopathology. To counter this process, we develop Glutoborin, a GLUT1-specific proteasome inhibitor, which disrupts MZM-B cell interactions, suppresses B cell activation, and alleviates systemic inflammation, ultimately protecting against CM. Mechanistically, proteomic analysis identifies anti-CD36 antibodies as key autoantibodies driving CM pathogenesis, triggering complement-dependent cytotoxicity in platelets and endothelial cells while activating macrophages through the CD36-TLR4 axis, further exacerbating inflammation. These findings redefine CM as an autoimmune-driven disease and highlight Glutoborin as a promising therapeutic strategy.
