The Role of Host Inflammatory Mediators As Biomarkers for Malaria Pathogenesis

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Malaria: Etiology, Pathogenesis and Treatments


Malaria pathogenesis results from a complex interplay of pro-inflammatory and antiinflammatory mediators produced as a result of innate responses following Plasmodium infection. These mediators interact with host tissues and organs resulting in damage and destruction that characterizes specific syndromes associated with red blood cell destruction, vascular endothelial disturbances, microvascular obstruction, respiratory distress, retinopathy, inflammatory responses to toxins and other parasite metabolites and placental tissue destruction. The malaria syndromes define uncomplicated malaria (UM), cerebral malaria (CM), placental malaria (PM), severe malarial anemia (SA), and severe malaria (SM). Approximately 515 million cases of malaria are reported annually with 1-3 million deaths occurring in children. Five Plasmodium species infect humans: P. falciparum, P. vivax P. malariae P. ovale and P. knowlesi. Plasmodium falciparum is the agent most associated with severe and fatal malaria. Pregnant women and children make up the most vulnerable groups to develop severe pathogenesis from malaria infection. Cytokines, chemokines, vascular endothelial proteins, angiogenic factors, and other host mediators make up important mediators of pathogenesis in the host. In addition, other non-immunologic host molecules, parasite proteins, metabolites and toxins may contribute to severe pathogenesis in the host. Determining which of the mediators enhance adverse outcomes for disease progression and poor disease prognosis as well as identifying those mediators with protective effects is an area of intense investigation in malaria research. The cytokines tumor necrosis factor alpha (TNFα), interleukin (IL)-12, IL-1ß, IL-10 and interferon gamma (IFNγ) are associated with the pathogenesis of cerebral malaria and severe anemia, with TNFα being strongly implicated with this form of malaria. Treatment of patients with neutralizing anti-TNFα antibodies was effective in resolving clinical symptoms. Low ratios of IL-10 to TNFα in serum correlate with severe anemia in contrast to high IL-10 to TNFα ratios seen in children with uncomplicated malaria. Levels of soluble ICAM-1, IL-1Ra, IL-2R, IL-4, IL-6, IL-6R, neopterin, angiopoeitin (ANG) 2 and TNFα are found to be highly elevated in patients with cerebral malaria, with TNFα being highly elevated in patients who died from cerebral malaria compared to patients with uncomplicated malaria. TNFα and ANG2 levels can predict poor prognosis with fatal outcomes in cases of cerebral malaria. A diagnostic test that is prognostic and capable of discriminating among the different malaria syndromes as well as distinguishing infections caused by non malaria pathogens will improve disease management of malaria and disease surveillance. A diagnostic test that incorporates host mediators of disease as well as parasite products and toxins would detect biomarkers of disease progression, diseases severity and development of cerebral malaria and will also be useful in determining the effectiveness of parasite clearance following drug treatment. In this chapter we examine studies performed to evaluate host mediators associated with malaria pathogenesis; uncomplicated malaria (UM), cerebral malaria (CM), placental malaria (PM), severe malarial anemia (SA), and severe malaria (SM) to determine the effectiveness of the mediators as biomarkers for malaria diagnosis. © 2012 Nova Science Publishers, Inc. All rights reserved.