AbstractMalaria continues to be responsible for substantial morbidity and mortality. There is a need for improved malaria elimination and treatment strategies. The aim of this thesis was to investigate innate host mechanisms in individuals naturally infected with Plasmodium parasites to identify potential targets for antiparasitic and adjunctive drugs and examine a potential site for a hidden parasite biomass. This thesis describes the roles of three innate host machineries in protection and pathogenesis – platelets, neutrophils and the spleen.
Using blood samples, analysis of platelet-parasite interactions in 376 Indonesian and Malaysian patients with and without falciparum, vivax, malariae or knowlesi malaria found that platelets play an important role in controlling parasitaemia by directly binding to and killing Plasmodium parasites via platelet factor-4 activity. In a subset of these patients, neutrophil extracellular traps (NETs) were increased in proportion to parasite biomass and disease severity, and may contribute to malaria pathogenesis. In asymptomatic P. falciparum infection, NETs may inhibit parasite growth.
Analyses of hospital records from 10,774 patients over a ten-year period in Papua, Indonesia, indicate that splenectomy increases the risk of clinical malaria, particularly from P. vivax. Potential reasons to explain this are discussed. In a smaller prospective cohort of splenectomy patients, 22 spleens were analysed for Plasmodium infection, with 21 found to have non-phagocytosed P. falciparum and/or P. vivax accumulating in the spleen. Splenic accumulation of immature reticulocytes and the patterns of parasite density, staging and distribution suggest that the spleen, in addition to its well-documented protective roles, may also be a site for parasite multiplication, sexual stage development, and potentially biomass-related pathogenesis.
Collectively, the findings in this thesis suggest that a) platelet-based peptides are novel candidates for malaria treatment, b) agents which reduce neutrophil activation and NET release may have potential as adjunctive therapies, c) splenectomy patients in regions co-endemic for vivax and falciparum malaria should be given malaria radical cure and prophylaxis, particularly in the early post-operative period, d) the human spleen sustains a significant proportion of non-phagocytosed biomass, particularly for P. vivax, which may not be fully identified/targeted in current diagnosis and treatment strategies, and modelling approaches, and e) immature reticulocytes are concentrated and undergo maturation in the human spleen, providing a potential source of target cells for P. vivax multiplication.
Note: Please note the thesis is embargoed till 11/04/2020.
|Date of Award||Nov 2018|
|Supervisor||Nicholas Anstey (Supervisor) & Tsin Yeo (Supervisor)|