Biomarkers measured in the blood can provide information about disease pathophysiology, diagnosis and prognosis. Pronounced proinflammatory responses are characteristic of severe malaria, and excessive activation of the immune system is central to the pathophysiology of both cerebral malaria and placental malaria. Severe malaria is characterized by cytoadherence of parasitized erythrocytes to the microvasculature; impaired tissue perfusion; dysregulated inflammatory responses; and activation of the complement system, mononuclear cells, and endothelium. Despite the availability of effective antimalarial drugs, the mortality rate in severe malaria remains unacceptably high. To glean further insight into malaria pathophysiology, we investigated host biomarkers of immune activation in the blood of subjects with different manifestations of severe disease. C5 has been identified as being necessary and sufficient for the development of experimental cerebral malaria. We hypothesized that C5a (a terminal component of the complement cascade with potent inflammatory properties) may mediate its action by inducing and exacerbating inflammatory processes in severe malaria, leading to endothelial activation and dysregulated angiogenesis. I tested this hypothesis in vitro, and found that C5a interacted with malaria toxin PfGPI to drive deleterious inflammatory and anti-angiogenic responses. As C5a and anti-angiogenic factor sFlt-1 have been implicated in models of pathologic pregnancies, we asked whether increased levels of C5a in subjects with placental malaria were associated with altered angiogenesis and poor birth outcomes. Our results suggest that C5a impairs angiogenic remodelling in placental malaria leading to vascular insufficiency and fetal growth restriction. Further, altered profiles of inflammatory and angiogenic biomarkers in the periphery may identify occult placental malaria infections. We extended these observations to cerebral malaria where similar pathogenic pathways contribute to disease pathophysiology. In adults and children with cerebral malaria, altered profiles of angiogenic proteins were associated with disease severity and mortality and represent putative diagnostic and prognostic biomarkers in severe malaria.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32064 |
| Date | 19 January 2012 |
| Creators | Conroy, Andrea |
| Contributors | Kain, Kevin C. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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