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* Molecular Immunopathology Unit, Bosch Institute, School of Medical Sciences and
School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, Australia;
Mycobacterial Research Division, Centenary Institute, Camperdown, New South Wales, Australia; and
Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, MA 02115
Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3–/– mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-
and lymphotoxin-
in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Health and Medical Research Council of Australia and the Sir Zelman Cowen Universities Fund (to N.H.H.), and National Institute of Health Grant NS044905 (to I.L.C.). J.M. was supported by an Australian Postgraduate Award. S.L.C. is a recipient of an Endeavour International Postgraduate Research Scholarship and was supported by an International Postgraduate Award. M.M. was a postdoctoral fellow from the Deutsche Forschungsgemeinschaft (Mu17-07/3-1) and also received support from the "Innovative Medical Research" fund, University of Münster. H.J.B. is a Rolf Edgar Lake Research Fellow of the Faculty of Medicine, University of Sydney.
2 Address correspondence and reprint requests to Prof. Nicholas H. Hunt, Molecular Immunopathology Unit, Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, Australia. E-mail address: nhunt{at}med.usyd.edu.au
3 Abbreviations used in this paper: CM, cerebral malaria; FMCM, fatal murine CM; BBB, blood-brain barrier; WT, wild type; KO, knockout; PbA, Plasmodium berghei ANKA; PbK, Plasmodium berghei K173; p.i., postinoculation; IHC, immunohistochemistry; NHS, normal horse serum; PRBC, parasitized RBC; HPRT, hypoxanthine guanine phosphoribosyltransferase; BSL, brain-sequestered leukocyte; NCM, non-CM; LCM, laser capture microdissection; ISH, in situ hybridization; LT-, lymphotoxin-.
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