Parasite genetic effects and host interactions in Plasmodium falciparum malaria

Thesis

Malaria remains a substantial public health threat. Over recent decades improvements in rates of mortality from Plasmodium falciparum malaria have been observed in Africa where most disease burden persists. This success however, is threatened by parasite counter evolution against anti-malarial drugs and recently approved vaccines for falciparum malaria. Human genetics has been extensively studied in terms of malarial disease. Comparatively little is understood about parasite genetic effects on disease outcomes, and their response to natural or vaccine induced host immunity. There is therefore a need to investigate parasite genetics and how they interact with the host’s in order to inform intervention strategies, control disease, and reach the eventual goal of elimination. This requires the generation of large datasets of host and parasite genetic information, alongside accurate phenotypic data, to infer how these factors influence disease outcomes.

In this thesis, I develop a new resource to investigate parasite and human genetic variation in malarial disease, using severe and mild cases collected in Gambian infants from 1988-90 (the ‘GAMCC’ resource). I integrate this with public datasets to perform powered, cross population analyses including an unbiased, genome-wide scan for parasite genetic effects on disease severity. This indicates a potential association on parasite chromosome 1 with evidence of replication but reveals minimal evidence of strong parasite genetic effects overall. I further investigate the recent finding that P. falciparum is evolving at loci known as Pfsa to counteract HbS-mediated resistance, identifying a novel putative region of interaction on parasite chromosome 2 (named Pfsa2B). I also uncover additional potential population-specific effects, highlighting the intricacy of HbS-Pfsa relationships. Through novel methods development I characterise complex structural variation at Pfsa3, which extends the potential that this might underlie the association of this region with HbS. My analyses provide important insights into host-pathogen interactions, opening possibilities for several future functional studies.

Authors: Forster, AJ

• DOI: 10.5287/ora-eoqqrx7vp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: host-pathogen interactions; sickle haemoglobin; genome-wide association studies; malaria; evolution; co-evolution; Plasmodium falciparum; The Gambia; structural variation
• Subjects: Genetics--Statistical methods; Malaria; Genomics; Evolution; Tropical medicine