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|Title: ||Var gene transcription and clinical disease manifestation in African P. falciparum malaria field isolates|
|Authors: ||Kyriacou, Helen M|
|Supervisor(s): ||Rowe, J A|
|Issue Date: ||2008|
|Abstract: ||The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant
surface antigens, encoded by the var gene family, play a crucial role in malaria
pathogenesis through mediating immunomodulation and host cell adhesion. Var
genes can be sub-grouped according to genetic or functional features. This thesis
examined var gene transcription of conserved groups of var genes in the context of
clinical malaria disease manifestation in African field isolates.
Analysis of var gene transcription in 26 P. falciparum field isolates from Malian
children revealed that field isolates from children with cerebral malaria show
significantly higher transcription of group A var genes than the field isolates from
children with equally high parasite burdens but no symptoms or signs of severe
malaria (hyperparasitaemia). These results suggest that group A var genes are
important determinants of parasite virulence and strengthen the growing body of
evidence associating group A var expression with severe disease in children.
Analysis of var gene transcription in six P. falciparum placental malaria field
isolates showed that var2csa was transcribed in all placental malaria field isolates,
but not in 10 childhood isolates examined. This finding, also reported in other recent
and subsequent studies, suggests that var2csa expression is a critical factor in the
onset of clinical malaria disease in pregnant women.
Examination of type 3 var gene transcription in laboratory and field isolates
established that these var genes were commonly transcribed in blood-stage parasites, and sequence analysis of the transcribed domains confirmed a very high level of
conservation across this var gene sub-family.
Finally, rosetting is a property of some group A PfEMP1 and is associated with
disease severity in African childhood malaria. Certain glycoconjugate compounds
can disrupt rosetting, possibly due to the functional similarities of interactions
between rosetting PfEMP1 and host rosetting ligands. A non-toxic compound
(curdlan sulfate) was found to be effective at disrupting rosettes in all 18 rosetting
field isolates examined, showing potential for use in treatment of severe malaria due
to rosetting P. falciparum isolates.
The findings presented in this thesis expand current knowledge of the role and
significance of var genes/PfEMP1 in P. falciparum malaria disease pathogenesis.
The work demonstrates the importance of continued research on var genes/PfEMP1
in further understanding this complex parasite, and ultimately in combating this
|Appears in Collections:||Biological Sciences thesis and dissertation collection|
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