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Infection and Immunity, September 2005, p. 5645-5653, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5645-5653.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Early Cytokine Production Is Associated with Protection from Murine Cerebral Malaria

Andrew J. Mitchell,1,{dagger} Anna M. Hansen,1,2,{dagger} Leia Hee,1 Helen J. Ball,1 Sarah M. Potter,1,{ddagger} John C. Walker,2 and Nicholas H. Hunt1*

Departments of Pathology,1 Medicine, University of Sydney, Sydney, Australia2

Received 21 December 2004/ Returned for modification 18 February 2005/ Accepted 9 May 2005

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, {gamma}{delta}-cell-depleted, and J{alpha}281–/– (NKT-cell-deficient) mice but absent from ß2-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.

* Corresponding author. Mailing address: University of Sydney, Department of Pathology, Medical Foundation Building (K25), 92-94 Parramatta Rd., Camperdown NSW 2042, Australia. Phone: 61-2-9036 3242. Fax: 61-2-9036 3286. E-mail: nhunt{at}med.usyd.edu.au.

Editor: J. F. Urban, Jr.

{dagger} A.J.M. and A.M.H. contributed equally to the work in this paper.

{ddagger} Present address: Département d'Immunologie, Institut Cochin, Institut National de la Santé et da la Recherche Médicale Unité 567, Paris, France.

Infection and Immunity, September 2005, p. 5645-5653, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5645-5653.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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