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 chandy2007.

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. chandy2007
 * 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 chandy2007.

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) chandy2007
 * Immune responses noted in murine CM studies chandy2007 :
 * 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. lovegrove2007.
 * endothelin-1 up-regulated (vasoconstrictor in brain) lovegrove2007
 * neuronal apoptosis (caspases, Fas) are hubs lovegrove2007.
 * X-receptor-alpha is hub (dimerizes with other peroxisome receptors). Natural substrate increases parasitized cell phagocytosis and decreases TNF-alpha production (good!) lovegrove2007.

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) chak2007
 * Cytokines:
 * IL8 - increased up-reg chak2007

References:
 * 1) chandy2007 pmid=17991710
 * 2) lovegrove2007 pmid=17991715
 * 3) chak2007 pmid=17383656


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