Changes in protein levels as markers of severe disease: an investigation of severe malaria

Gitau, Evelyn Nungari (2008). Changes in protein levels as markers of severe disease: an investigation of severe malaria. PhD thesis The Open University.



Compounds directly involved in the pathogenesis of cerebral malaria (CM) remain unclear due to lack of robust methods of identifying and quantifying proteins expressed in low abundance. New developments in proteomics have now made it possible to identify low abundant proteins and provided new tools for studying host-parasite interactions. With these new tools, it may be possible to identify proteomic signatures for patients with various complications associated with severe malaria. A global proteomic strategy was used to identify differentially expressed proteins in archived plasma and CSF drawn from children diagnosed with cerebral malaria (CM) compared to those with acute bacterial meningitis (ABM) and slide negative encephalopathy (EN). Samples were first separated using two-dimensional gel electrophoresis (2-DE) or two-dimensional liquid chromatography (2D-LC) and analysed using mass spectrometry. The data collected was analyzed using various bio-informatics tools. Finally, a CM mass profile was created using MALDI-ToF mass spectrometry. Averages of about 150 spots per gel were resolved from CSF from CM and EN patients and 80 spots from ABM patients. In the gels from the CM and EN groups, 45 human proteins were found whilst 20 human proteins were unique to ABM compared to CM. For CSF, a total of 202 human proteins were identified using the 2D-LC system. Of these 13 were unique to CM, 124 to ABM and 32 to EN. 6 proteins were found in both CM and ABM and 18 were found in EN and ABM. 9 proteins were common to all 3 disease groups. A total of 66 P. falciparum proteins were identified but of these 48 were hypothetical proteins. Of the non-hypothetical proteins, 2 were found in both CM and ABM and the rest were found only in ABM. Results show that proteomics can be used to create protein profiles of different disease groups. Majority of the human proteins identified by 2-DE were found to be high abundant proteins found in CSF and plasma. The use of 2D-LC enabled the identification of more low abundant proteins but some of the P. falciparum proteins identified by 2-DE were not seen in the 2D-LC method. Majority of the human proteins found were acute phase response plasma proteins including common circulating proteins such as albumin and apolipoproteins, blood transporters and binding proteins, protease inhibitors, enzymes, cytokines and hormones, and channel and receptor-derived proteins. There seems to be a correlation between the number of proteins found in the CSF and the level of blood brain barrier break down.

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