Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency.
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-gamma and lymphotoxin-alpha 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.
Miu
Jenny
J
Molecular Immunopathology Unit, Bosch Institute, School of Medical Sciences, University of Sydney, New South Wales, Australia.
Mitchell
Andrew J
AJ
Müller
Marcus
M
Carter
Sally L
SL
Manders
Peter M
PM
McQuillan
James A
JA
Saunders
Bernadette M
BM
Ball
Helen J
HJ
Lu
Bao
B
Campbell
Iain L
IL
Hunt
Nicholas H
NH
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002196:Capillaries / Q000737:chemistry; D054357:Chemokine CXCL10 / Q000235:genetics; D054370:Chemokine CXCL9 / Q000235:genetics; D018925:Chemokines / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010963:Plasmodium falciparum; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000502:physiology*
D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3