Cerebral malaria in mice: interleukin-2 treatment induces accumulation of gammadelta T cells in the brain and alters resistant mice to susceptible-like phenotype.
In this study, we report that infection with Plasmodium yoelii 17XL, a lethal strain of rodent malaria, does not result in death in the DBA/2 strain of mice. In contrast to BALB/c mice, DBA/2 mice developed significantly less parasitemia and never manifested symptoms of cerebral malaria (CM) on infection with this parasite. Moreover, the histological changes evident in the brain of susceptible BALB/c were absent in DBA/2 mice. Interestingly, the resistant DBA/2 mice when treated with recombinant interleukin (IL)-2, were found to develop CM symptoms and the infection became fatal by 6 to 8 days after infection. This condition was associated with an augmented interferon-gamma and nitric oxide production. Unexpectedly, IL-10 levels were also elevated in IL-2-treated DBA/2 mice during late stage of infection (at day 6 of infection) whereas the inverse relationship between IL-10 and interferon-gamma or nitric oxide was maintained in the early stage of infection (at day 3 after infection). The level of tumor necrosis factor-alpha production was moderately increased in the late phase of infection in these mice. Histology of brain from IL-2-treated mice demonstrated the presence of parasitized erythrocytes and infiltration of lymphocytes in cerebral vessels, and also displayed some signs of endothelial degeneration. Confocal microscopical studies demonstrated preferential accumulation of gammadelta T cells in the cerebral vessels of IL-2-treated and -infected mice but not in mice treated with IL-2 alone. The cells recruited in the brain were activated because they demonstrated expression of CD25 (IL-2R) and CD54 (intercellular adhesion molecule 1) molecules. Administration of anti-gammadelta mAb prevented development of CM in IL-2-treated mice until day 18 after infection whereas mice treated with control antibody showed CM symptoms by day 6 after infection. The information concerning creating pathological sequelae and death in an otherwise resistant mouse strain provides an interesting focus for the burden of pathological attributes on death in an infectious disease.
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Immunologie et Génétique des Maladies Parasitaires, INSERM U399, Faculté de Médecine, Université de la Mediterranee, La Timone, Marseille, France. h.azizul@medecine.univ-mrs.fr
Echchannaoui
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Seguin
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Schwartzman
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Kasper
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D020022:Genetic Predisposition to Disease; D007376:Interleukin-2 / Q000494:pharmacology; D016779:Malaria, Cerebral / Q000469:parasitology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018613:Microscopy, Confocal; D009573:Nitrites / Q000378:metabolism; D010641:Phenotype; D010967:Plasmodium yoelii; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D009573:Nitrites; D016692:Receptors, Antigen, T-Cell, gamma-delta