The use of population genomics to identify targets of immune selection on parasites
Professor David Conway, London School of Hygiene and Tropical Medicine, UK
While the first human genome was still being sequenced, malaria parasite genomics was successfully argued as a high priority for funding to enable discovery of vaccine candidate antigens. This stimulated increased research on malaria, generating new understanding of cellular and molecular mechanisms of infection and immunity. I will explain how approaches in parasite population genomics are helping to identify antigens to be pursued as promising targets. By statistically analysing sequences of whole genomes from many different infections, it is possible to identify genes that appear to be subject to particular selective processes, indicating ways in which parasites interact with humans and mosquitoes. Usefully, it helps identify some of the important parasite antigen targets of immunity, as particular patterns of selection result from acquired immune responses in humans. We have tested some of these findings by looking at human antibodies to engineered recombinant antigens in laboratory experiments, to see whether they inhibit the parasite in culture or if they are associated with being protected against malaria in epidemiological studies, showing several antigens to be supported as potential candidate targets. Downstream of initial inferences, identification of the most promising antigens for a vaccine requires detailed functional analyses and multiple population-based studies, which will be well illustrated by the work of the other speakers.
Naturally acquired immunity to malaria: identifying targets, understanding mechanisms
Professor Faith Osier, KEMRI Wellcome Trust Research Programme, Kenya
The targets and mechanisms underlying naturally acquired immunity against the clinical consequences of Plasmodium falciparum malaria in humans are not well understood. Although passive transfer studies demonstrated the therapeutic effect of antibodies, the large number of proteins in the parasite proteome has made it difficult to distinguish antibodies that actually contribute to immunity from those merely related to parasite exposure. Compounding this has been the difficulty in producing large panels of natively refolded recombinant proteins for testing in immunological studies. Consequently, only a small proportion of the parasite proteome has been interrogated with regards to human immunity, and an even smaller proportion has been tested in clinical trials. Our studies indicate that there are potentially many more antigens that could contribute to human immunity, and that combinations of antibody responses to these antigens may be highly effective in protecting against malaria. We also demonstrate that the antibody-dependent phagocytosis of merozoites by monocytes closely mirrors the acquisition of immunity in African children and is strongly associated with a reduced risk of malaria. These studies will be extended to other locations in Africa experiencing varying malaria transmission intensity, tested in the context of controlled human challenge infections, and ultimately contribute to the development second-generation malaria vaccines.
New molecular and cellular approaches to understanding erythrocyte invasion by malaria parasites
Dr Julian Rayner, Wellcome Trust Sanger Institute, UK
Plasmodium parasites have complex life cycles, but all the symptoms and pathology of malaria occurs during the erythrocytic phase. During this phase Plasmodium parasites recognise and invade human erythrocytes, where they become shielded from the immune system and use haemoglobin as a source of food to fuel their replication. The process of erythrocyte invasion is therefore critical for parasite survival and malaria pathology. In P. falciparum, the species that causes almost all human malaria mortality, recognition can occur through multiple redundant cell surface protein-protein interactions. Recognition is followed by an active entry process, driven by an actin-myosin motor anchored to the parasite cytoskeleton. The morphological outlines of erythrocyte invasion have been known for several decades, but the molecular details are still being elucidated. In particular, while many P. falciparum proteins have been identified as being involved in erythrocyte recognition and invasion, in the majority of cases we do not know the receptors that they bind to. In collaboration with Dr Gavin Wright at the Wellcome Trust Sanger Institute we have been applying new protein-protein interaction screening approaches to identify new interactions involved in invasion. We are now coupling these approaches with advanced microscopy technologies, including using laser tweezers to measure the force of interaction between erythrocytes and parasites. These approaches are helping to identify and prioritise new vaccine candidates, and feed directly into Dr Faith Osier’s work on understanding natural acquired immunity to malaria.