Abstract
BackgroundMalaria 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.MethodsThe 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.ResultsRANTES (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 d istal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls.ConclusionThe upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria.
Highlights
Malaria afflicts 300–500 million people causing over 1 million deaths globally per year
Plasmodium yoelii 17XL murine malaria All the mice infected with P. yoelii 17XL parasites developed malaria-related-symptoms, which included the appearance of ruffled fur and shivering at peak parasitaemia by day eight post-infection (Figure 1)
The results of RT-polymerase chain reaction (PCR) analysis indicate that by days 6 through 8 post-infection, Messenger RNA (mRNA) expression of RANTES is significantly up-regulated (p < 0.002) in infected mice compared with controls, indicating that it is involved in the immunopathogenesis in P. yoelii 17XL-infected mouse
Summary
Malaria afflicts 300–500 million people causing over 1 million deaths globally per year. Other more recent studies, using malaria animal models, showed that experimental cerebral malaria (ECM) was induced in perforin-deficient mice (PFP-/-) after adoptive transfer of cytotoxic CD8+ T cells from infected C57BL/6 mice, which were directed to the brains of PFP-/-mice This specific recruitment involved chemokines and their receptors, and indicated that lymphocyte cytotoxicity and trafficking are key players in ECM [10]. While CCR2 was not observed to be essential for the development of ECM [13], CCR5 deficiency in mice reportedly decreased susceptibility to ECM [9] These studies, together, support the hypothesis that leukocyte recruitment by chemokine and chemokine receptor interactions play a role in the pathogenesis of malaria in these animal models. We analysed the alterations in immunomodulator gene expression in brain samples of P. yoelii 17XL-infected mice using cDNA microarray screening, coupled with analysis of temporal expression patterns of RANTES and its corresponding receptors, CCR1, CCR3 and CCR5, in brain samples and plasma of P. yoelii 17XL-infected mice to identify and characterize the role of these immunomodulators during rodent malaria
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