Role of CD40-CVD40L in mouse severe malaria.
We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in +/+ mice, but markedly decreased in CD40-/- or in CD40L-/- mice, as well as in +/+ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected +/+, but not in CD40-/- mice. Thrombocytopenia was less severe in CD40-/- mice than in the +/+ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40-/- or in CD40L-/- mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected +/+ or CD40-/- mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption.
Piguet
P F
PF
Department of Pathology, University of Geneva, 1 rue M. Servet, CMU, 1211 Geneva, Switzerland. pierre.piguet@medecine.unige.ch
Kan
C D
CD
Vesin
C
C
Rochat
A
A
Donati
Y
Y
Barazzone
C
C
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei; D010976:Platelet Count; D012333:RNA, Messenger / Q000235:genetics; D013921:Thrombocytopenia; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019013:CD40 Antigens; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand