Plasmodium yoelii 17XL infection up-regulates RANTES, CCR1, CCR3 and CCR5 expression, and induces ultrastructural changes in the cerebellum.
BACKGROUND
Malaria afflicts 300-500 million people causing over 1 million deaths globally per year. The immunopathogenesis of malaria is mediated partly by co mplex cellular and immunomodulator interactions involving co-regulators such as cytokines and adhesion molecules. However, the role of chemokines and their receptors in malaria immunopathology remains unclear. RANTES (Regulated on Activation Normal T-Cell Expressed and Secreted) is a chemokine involved in the generation of inflammatory infiltrates. Recent studies indicate that the degradation of cell-cell junctions, blood-brain barrier dysfunction, recruitment of leukocytes and Plasmodium-infected erythrocytes into and occlusion of microvessels relevant to malaria pathogenesis are associated with RANTES expression. Additionally, activated lymphocytes, platelets and endothelial cells release large quantities of RANTES, thus suggesting a unique role for RANTES in the generation and maintenance of the malaria-induced inflammatory response. The hypothesis of this study is that RANTES and its corresponding receptors (CCR1, CCR3 and CCR5) modulate malaria immunopathogenesis. A murine malaria model was utilized to evaluate the role of this chemokine and its receptors in malaria.


METHODS
The alterations in immunomodulator gene expression in brains of Plasmodium yoelii 17XL-infected mice was analysed using cDNA microarray screening, followed by a temporal comparison of mRNA and protein expression of RANTES and its corresponding receptors by qRT-PCR and Western blot analysis, respectively. Plasma RANTES levels was determined by ELISA and ultrastructural studies of brain sections from infected and uninfected mice was conducted.


RESULTS
RANTES (p < 0.002), CCR1 (p < 0.036), CCR3 (p < 0.033), and CCR5 (p < 0.026) mRNA were significantly upregulated at peak parasitaemia and remained high thereafter in the experimental mouse model. RANTES protein in the brain of infected mice was upregulated (p < 0.034) compared with controls. RANTES plasma levels were significantly upregulated; two to three fold in infected mice compared with controls (p < 0.026). Some distal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls.


CONCLUSIONS
The upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria.
Sarfo
Bismark Y
BY
Parasitology Unit, Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG581, Legon, Accra, Ghana. bsarfo@noguchi.mimcom.net
Armah
Henry B
HB
Irune
Ikovwaiza
I
Adjei
Andrew A
AA
Olver
Christine S
CS
Singh
Shailesh
S
Lillard
James W
JW
Stiles
Jonathan K
JK
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002531:Cerebellum / Q000473:pathology / Q000648:ultrastructure*; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000502:physiology; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007155:Immunologic Factors / Q000502:physiology; D008288:Malaria / Q000276:immunology* / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010967:Plasmodium yoelii / Q000254:growth & development / Q000472:pathogenicity; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000502:physiology; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
C515300:CCR1 protein, human; C515350:CCR3 protein, human; C515301:Ccr1 protein, mouse; C515351:Ccr3 protein, mouse; D018946:Chemokine CCL5; D017931:DNA Primers; D007155:Immunologic Factors; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine