Biology of malarial liver stages: implications for vaccine design.
The molecular events controlling sporozoite invasion and exo-erythrocytic (EE) development within hepatocytes are largely not understood, and EE parasites are probably better defined immunologically than biologically. The observation that the Plasmodium falciparum sporozoite antigen TRAP (thrombospondin-related anonymous protein) contains multiple adhesive domains that recognize endothelial and hepatocyte receptors indicates that, like leucocyte passage across capillaries, sporozoite invasion probably involves a co-ordinated interaction between sporozoite and hepatic molecules. The parallel with leucocyte extravasation is strengthened by the finding that TRAP contains a functional, integrin-like, I domain. EE parasites are an important target of immunity elicited by irradiated sporozoites, and much current effort is focused on developing malaria vaccines targeting EE parasites. Only one EE-specific antigen, liver-stage antigen 1 (LSA-1), is known to be expressed during EE development and may contribute to protective immunity elicited by irradiated P. falciparum sporozoites. In a study in Papua New Guinea, resistance to P. falciparum infection correlated with CD8+ T-cell interferon-gamma responses to an LSA-1 epitope that contains an HLA A11-restricted sequence. Since A11 is > 40% frequent in this population it is reasonable to suggest that, as with B53 responses to LSA-1 in The Gambia, P. falciparum has driven genetic selection of certain HLA haplotypes, as proposed by Haldane nearly 50 years ago. LSA-1 is thus an important vaccine candidate, and is being expressed in bacterial and phage vectors.
School of Biology, University of Leeds, U.K. m.r.hollingdale@leeds.ac.uk
M R
MR
Hollingdale
C J
CJ
McCormick
K G
KG
Heal
A W
AW
Taylor-Robinson
P
P
Reeve
R
R
Boykins
J W
JW
Kazura
D000818:Animals; D000953:Antigens, Protozoan / Q000032:analysis; D006801:Humans; D008099:Liver / Q000469:parasitology*; D017780:Malaria Vaccines; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000276:immunology; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology
D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; C069428:thrombospondin-related adhesive protein, protozoan