Cerebral malaria (CM) is a severe neurological complication of malaria infection that
results from interrelated pathologies. Despite extensive research efforts, the
mechanism of the disease is not completely understood. Clinical studies, postmortem
analysis, and animal models have been the main research arenas in CM. In this thesis,
shotgun proteomics approach was used to further understand the pathology of human
and experimental CM.
The mechanism by which CM turns fatal is yet to be identified. A clinical
proteomics study was conducted on pooled plasma samples from children with
reversible or fatal CM from the Gambia. The results show that depletion of
coagulation factors and increased levels of circulating proteasomes are associated
with fatal pediatric CM. This data suggests that the ongoing coagulation during CM
might be a disseminated intravascular coagulation state that eventually causes
depletion of the coagulation factors leading to petechial hemorrhages. In addition, the
mechanism(s) by which blood transfusion benefits CM in children was investigated.
To that end, the concentration and multimerization pattern of von-willebrand factor,
and the concentration of haptoglobin in the plasma of children with CM who received
blood transfusions were measured.
In addition to clinical studies, experimental cerebral malaria (ECM) in mice
has been long used as a model for the disease. A shotgun proteomics workflow was
optimized to identify the proteomic signature of the brain tissue of mice with ECM.Because of the utmost importance of membrane proteins in the pathology of the
disease, sample fractionation and filter aided sample preparation were used to recover
them. The proteomic signature of the brains of mice infected with P. berghei ANKA
that developed neurological syndrome, mice infected with P. berghei NK56 that
developed severe malaria but without neurological signs, and non-infected mice, were
compared to identify CM specific proteins. Among the differentially expressed
proteins in mice that developed neurological signs, coagulation and acute-phase
proteins were enriched. The data are in accordance with data from the clinical study.
Taken together, the results support the role of coagulation and platelets adhesion in
the pathogenesis of the disease.
|Date of Award||Jul 2012|
|Original language||English (US)|
- Biological, Environmental Science and Engineering
|Supervisor||Arnab Pain (Supervisor)|
- Cerebral Malaria
- Experiments Malaria