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Title: Antigen expression and host-parasite interactions of Plasmodium falciparum infections in Malawian paediatric patients
Author: Tembo, Dumizulu
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Introduction: The process of sequestration involving specific cytoadhesion between parasite ligands expressed on the surface of the parasitised red blood cells (pRBC) and host vascular endothelium contributes to pathogenesis of severe falciparum malaria. A major polymorphic surface antigen implicated in cytoadhesion is the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the var multigene family that is sub-divided into three main groups: A, B and C, according to sequence similarities in coding and non-coding sequences. PfEMP1 has variant adhesive phenotypes, some of which interact with ABO blood groups to form rosettes and some involved in apparent formation of platelet-mediated clumps of infected erythrocytes that are thought to contribute to disease severity. With heavy HIV burden concentrating in areas with high malaria rates, co-infections are common. Both HIV and malaria interact with the host immune system, resulting in a complex activation of immune cells and subsequent dysregulated production of cytokines and antibodies. However, there is limited information on the molecular mechanisms of interaction between the two infections. Methods: Real time PCR was used to: 1) compare abundance of the three main var groups and measure the level of cytokine production and receptor expression utilising the resources of a clinicopathological study of 20 Malawian fatal paediatric malaria patients divided into three diagnostic groups: circulating and sequestered parasites (CM1); circulating and sequestered parasites plus perivascular pathology (CM2) and parasitaemic control (PC) groups; and 2) determine the effect of host ABO blood group on expression of var/PfEMP1 subtypes mediating platelet-mediating clumping in 65 Malawian paediatric patients with uncomplicated malaria (UM). Results: While there were no significant associations between ABO blood antigen groups with the clumping phenotype in UM patients, an abundance of var upsA and C transcripts were expressed in CM2 and the PC (p ≤ 0.001) groups. However, a very different expression pattern was observed in the CM1 group, which were mostly HIV positive (80%), with var gene group upsB being more abundant than in the other two diagnostic groups ( p ≤ 0.001). This result was supported by different cytokine/receptor upregulation between HIV positive and HIV negative children, with significant upregulation of TNF in HIV negative children (p ≤ 0.05). Conclusions: This data suggests that perivascular pathogenesis in naturally infected children is associated with differential var gene expression in the body. HIV disruption of cytokine release affects receptor regulation and influences parasite antigen expression.
Supervisor: Montgomery, Jacqui; Craig, Alister; Mandala, Wilson Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available