Role of CD40-CD40L in mouse severe malaria

We explored the role of CD40-CD40L (CD154) in the severe malaria elicited b y Plasmodium berghei anka infection in mice. Mortality was > 90% by day 8 a fter 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 bloo d-brain barrier was evident in infected +/+, but not in CD40-/- mice. Throm bocytopenia was less severe in CD40-/- mice than in the +/+ controls. Seque stration of macrophages in brain venules and alveolar capillaries was reduc ed in CD40-/- or in CD40L-/- mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD 40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infe cted mice whereas CD40L was increased in the lung. Tumor necrosis factor pl asma levels were similarly increased in infected +/+ or CD40-/- mice. Expre ssion of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria req uires CD40-CD40L interaction that contributes to the breakdown of the blood -brain barrier, macrophage sequestration, and platelet consumption.