This is attrib uted to decreased cytoadherence at lower body tempera ture, which assists anti malarial drugs in clearing ring stage parasites www.selleckchem.com/products/GDC-0449.html before they mature and cytoadhere. Fur ther experimental work is necessary to study if this is due to the effect of antipyretics on the trafficking of ETRAMP and KAHRP resulting in decreased PfEMP1 presentation. Activated platelets act as bridges between pRBCs and endothelial cells, allowing the binding of pRBC to the endothelium devoid of cytoadherence receptors. The MSP 1 gpIIIa interaction might play a crucial role in platelet activation, either via complex formation with MSP 6 MSP 7 or through contact with pRBCs, thus influencing systemic inflammation in CM. Antibody mediated blocking of the activity of gpIIb IIIa in vitro has revealed decreased platelet activation.
Other studies also show lowered antibody response to MSP 1 MSP 6 MSP 7 in CM patients when compared with non affected patients. Lowered antibody response to GPI anchor has also been reported in CM non survivors when com pared to the CM survivors. Hence, the MSP 1 gpIIIa interaction could indicate a novel mechanism of platelet activation by MSP 1. Platelet activation is also associated with tissue factor expression on the platelet surface. TF expression leads to amplification of the coagula tion cascade resulting in the consumption of coagulation factors. Platelet activation via MSP 1 and gpIIIa might thus also play a role in TF expression on the platelet sur face causing amplification of the coagulation cascade, leading to haemostasis dysfunction.
Haemostasis dysfunction during CM culminates in increased endothelial hemorrhage resulting in leakage of plasma proteins, proinflammatory cytokines and parasite factors across the BBB. This influx of foreign substances activates the microglial cells, resident macrophages of the brain and spinal cord. Upon activation, they release proinflammatory cytokines which damage astrocytes and glial cells that are crucial for BBB maintenance. In addition to the damage caused by this cytotoxic environ ment, it was hypothesized that the interaction between HSA and the TGF B receptors TGFBR1 and TGFBR2 could result in astrocyte dysfunction, followed by sei zures and neuronal death. When mapping of the interactome, an interesting observation was the dual behaviour of TGF B.
On the one hand, it has a protective effect on the host during the pathogenesis of CM due to its anti inflammatory prop erty. During the release of TGF B mediated by para site derived products such as PfTRAP, TGF B down regulates the proinflammatory cytokine TNF and up reg ulates the anti inflammatory GSK-3 cytokine IL 10. On the other hand, activated platelets locally release TGF B that synergizes with TNF in creating a proinflammatory con dition leading to BBB disruption. Increased activa tion of TGF B during early stages of the disease leads to reduced parasite clearance time.