Splenic macrophage-B cell axis drives systemic autoimmune-like pathology in Cerebral Malaria

  • Nat Commun. 2026 Jun 27. doi: 10.1038/s41467-026-74882-4.
Xin Sun  #  1 ,  Ridong Li  #  1 ,  Weixuan Wang  #  1 ,  Danli Yang  #  1 ,  Wenyu Tian  1 ,  Xin Zhang  1 ,  Linjiang Han  1 ,  Xuyang Zhao  1 ,  Xiaoyan Xing  2 ,  Runtao Li  3 ,  Yuhui Li  2 ,  Jing He  2 ,  Rui Song  4 ,  Fuping You  5 ,  Dan Lu  6
Affiliations
  • 1. Institute of Systems Biomedicine, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing Key Laboratory of Advanced Pharmaceutical Preparation, Peking University, Beijing, China.
  • 2. Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 4. National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China. [email protected].
  • 5. Institute of Systems Biomedicine, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing Key Laboratory of Advanced Pharmaceutical Preparation, Peking University, Beijing, China. [email protected].
  • 6. Institute of Systems Biomedicine, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing Key Laboratory of Advanced Pharmaceutical Preparation, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 42364976 DOI: 10.1038/s41467-026-74882-4
Abstract

Cerebral malaria (CM) is a severe complication of Plasmodium Infection, classically attributed to Parasite sequestration and neuroinflammation. Here, we uncover a spleen-centered humoral autoimmune circuit that drives CM pathology. Proteomic analyses identify CD36 as a dominant host-derived antigen enriched in infected red blood cells (iRBCs), triggering anti-CD36 autoantibody production in patients with falciparum malaria. Although contributing to iRBCs clearance, these autoantibodies also target other CD36-expressing cells, thereby driving thrombocytopenia, endothelial injury, and macrophage activation, ultimately amplifying systemic inflammation. Mechanistically, Plasmodium Infection recruits Ly6c+GLUT1hi Macrophages to the spleen through the CCL2-CCR2 axis. These Macrophages exhibit elevated Proteasome activity and drive B cell activation and anti-CD36 antibody production. Targeting Ly6c+GLUT1hi Macrophages, we develop Glutoborin, a GLUT1-directed Proteasome inhibitor that preferentially suppresses their function, reduces autoantibody production, and alleviates CM-associated pathology in vivo. Together, these findings establish a spleen-centered anti-CD36 autoimmune circuit as a key driver of CM and nominate Ly6c+GLUT1hi Macrophages as therapeutic targets.

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