Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria

Previous studies demonstrated that Plasmodium yoelii 17XL, a lethal strain of rodent malaria, causes a syndrome in SW mice that resembles human cerebr al malaria. The mouse brain pathology is characterized by cytoadherence of parasitized erythrocytes. Here, the possible mechanisms mediating cerebral malaria in this model were studied and the results were compared with a non lethal strain of this parasite, P. yoelii 17XNL (nonlethal), which does not cause cerebral malaria. Immunostaining for intercellular adhesion molecule -1 (ICAM-1) revealed an increase in expression of this protein in the small venules and capillaries of the brains of infected mice that increased with time after infection. Staining was more pronounced during the lethal infec tion than the nonlethal infection. Some staining with monoclonal antibody t o vascular cell adhesion molecule-1 was also observed, but it was quantitat ively less than ICAM-1 staining and was limited to larger venules. During t he lethal infection, levels of tumor necrosis factor-alpha (TNF-alpha) incr eased rapidly, peaking on day 4. In contrast, mice infected with nonlethal P. yoelii had a slower serum TNF-alpha response that peaked on day 10, prio r to the maximum parasitemia. In addition, mice with a targeted disruption of the TNF-alpha gene (TNF-alpha-/- mice) were infected with the lethal and nonlethal strains of P. yoelii 17X. The TNF-alpha-/- mice infected with th e nonlethal parasite had significantly higher levels of parasitemia than co ntrols, whereas TNF-alpha-/- mice infected with the lethal strain had sligh tly higher levels of infected erythrocytes but were equally susceptible to death from this infection. Thus, TNF-alpha does not appear to be essential in mediating death. These results demonstrate that P. yoelii 17XL infection has features in common with human cerebral malaria and suggest that this m odel may be useful in testing strategies to alleviate this syndrome.