Cellular immune responses to the cysteine-rich interdomain region-1-alpha (CIDR-1α) of Plasmodium falciparum erythrocyte membrane protein 1 (PFEMP-1)

Ndung'u, Francis Maina (2005). Cellular immune responses to the cysteine-rich interdomain region-1-alpha (CIDR-1α) of Plasmodium falciparum erythrocyte membrane protein 1 (PFEMP-1). PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000101a1

Abstract

During the erythrocytic cycle, the malaria parasite Plasmodium falciparum, inserts its own molecules into the membrane of the infected red blood cell (Pf- iRBC). One of these molecules, Plasmodium falciparum Erythrocyte Membrane Protein-1 (PfEMP-1) belong to a large gene family (Var) with around 60 copies per haploid genome distributed in all chromosomes. Far genes show extreme diversity but all contain a number of domains displaying homology to the previously described Duffy Binding Like (DBL) molecules or in the case of CD36 binding, to another relatively conserved region, the Cysteine Rich Interdomain Region (CIDR-la). Due to their surface location, antigenicity and involvement in pathogenesis of severe malaria, these molecules form an important candidate for a malaria vaccine.
Previously, we studied the CD4 T cell response to relatively conserved recombinant segments expressed from three different domains of PfEMP-1: EXON 2, CIDR-la and DBL-a. We measured in vitro CD4 T cell proliferation, Interferon- (IFN)-y and Interleukin (IL)-10 production in peripheral mononuclear cells (PBMC). Only responses to EXON 2 and DBL-a were associated with exposure to malaria. The response to CIDR-la was striking in that both exposed and non-exposed donors responded similarly. In the studies presented here, the cell phenotypes responding to CIDR-la, the cytokines they make and their kinetics were analysed. In addition, the requirements for HLA restriction and T Cell Receptor (TCR) engagement for the CD4 T cell and IFN-y responses were investigated.
CIDR-la activated human myeloid DCs in either whole PBMC or separately (isolated DC) to produce IL-10, IL-12 and IL-18. The IL-10 and IL-18 responses could be reproduced with intact Pf-iRBC. IL-10 and IL-12 were produced with different kinetics highlighting the need for time course experiments in studies investigating cytokine production by DCs. The IFN-y response to CIDR-la in malaria-unexposed individuals was largely independent of MHC class II/TCR engagement whilst both the CD4 T cell and IFN-y responses in malaria-exposed donors were MHC class II restricted. These findings suggest that the CD4 T cell response to CIDR-la in malaria semi-immune adults has an element of immunological memory on top of the pre-existing responses seen in the malaria- unexposed adult.