User:Matthew Whiteside/Notebook/Malaria Microarray/2009/01/27

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Malaria Task 3.2 Reading up on what is known about cerebral pathogenesis General Disease Symptoms Studies to date suggest that CM is attributable to a combination of local brain tissue damage from microvascular ischemia and hypoxia and more global brain injury caused by the host immune response to the parasite. These studies rely on testing pre-determined factors (e.g. parasite load) and for humans, rely on autopsy studies [1]. Comparison between human disease and murine models Different parasites cause CM disease in humans and mice. Plasmodium falciparum in humans: <40% mortality neurological symptoms:disturbed gait and transient limb paralysis, eventually coma. induces adherence of infected red blood cells to vascular endothelium. Plasmodium berghei ANKA (PbA) or Plasmodium yoelii in mice strains C57BL or CBA: 100% mortality neurological impairment and coma primarily sequestration of leukocytes and some red blood cells to vascular endothelium. PbA & DBA mouse strain: mice can survive, develop neurological impairment. No coma though. [1] Pitfalls in microarray comparison: CM-resistant and CM-susceptible mice have very different responses (little overlap in genes). Different mice strains in general have very different responses [1]. Pathways Involved in Murine CM pathogenesis (conclusions from microarray or other studies) immune system response involved (not just hypoxia resulting from sequestration of RBCs in brain) [1] Immune responses noted in murine CM studies [1]: TNF-alpha production blood-brain barrier breakdown (likely due to immune resp) endothelial damage VCAM-1 and ICAM-1 cell adhesion molecules ICAM-1 cell adhesion up-regulated Nitric Oxide INF-gamma up-regulated. Evidence of interferon-response elem genes being up-reg, includes signalling genes STAT1 IRF1, and indicuble genes Cxcl10. [2]. endothelin-1 up-regulated (vasoconstrictor in brain) [2] neuronal apoptosis (caspases, Fas) are hubs [2]. X-receptor-alpha is hub (dimerizes with other peroxisome receptors). Natural substrate increases parasitized cell phagocytosis and decreases TNF-alpha production (good!) [2]. Pathways Involved in Human CM pathogenesis (conclusions from in vitro microarray or other studies) ICAM-1 cell adhesion surface protein (low TNF-alpha is required) [3] Cytokines: IL8 - increased up-reg [3] References: John CC. Cerebral malaria pathogenesis: what can we learn from microarray analysis?. Am J Pathol. 2007 Dec;171(6):1729-32. DOI:10.2353/ajpath.2007.070917 | Lovegrove FE, Gharib SA, Patel SN, Hawkes CA, Kain KC, and Liles WC. Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria. Am J Pathol. 2007 Dec;171(6):1894-903. DOI:10.2353/ajpath.2007.070630 | Chakravorty SJ, Carret C, Nash GB, Ivens A, Szestak T, and Craig AG. Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: pathogenic or protective?. Int J Parasitol. 2007 Jul;37(8-9):975-87. DOI:10.1016/j.ijpara.2007.02.006 |