Early cytokine production is associated with protection from murine cerebral malaria.
Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. berghei K173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-gamma) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-gamma, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN-gamma production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN-gamma at 24 h p.i., in a manner similar to animals infected with P. berghei K173 alone. These coinfected mice failed to develop CM. In addition, in a low-dose P. berghei K173 infection model, protection from CM was associated with early production of IFN-gamma. Early IFN-gamma production was present in NK-cell-depleted, gammadelta-cell-depleted, and Jalpha281(-/-) (NKT-cell-deficient) mice but absent from beta2-microglobulin mice that had been infected with P. berghei K173. Taken together, the results suggest that the absence of a regulatory pathway involving IFN-gamma and CD8(+) T cells in P. berghei ANKA infection allows the development of cerebral immunopathology.
Mitchell
Andrew J
AJ
University of Sydney, Department of Pathology, Medical Foundation Building, 92-94 Parramatta Rd., Camperdown NSW 2042, Australia.
Hansen
Anna M
AM
Hee
Leia
L
Ball
Helen J
HJ
Potter
Sarah M
SM
Walker
John C
JC
Hunt
Nicholas H
NH
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004198:Disease Susceptibility / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei / Q000276:immunology*; D013997:Time Factors; D001613:beta 2-Microglobulin / Q000502:physiology
D016207:Cytokines; D001613:beta 2-Microglobulin; D007371:Interferon-gamma