AbstractIntroduction: The global health burden of malaria is estimated at 200 million cases annually. Efforts to reduce malaria cases have recently stalled, calling for an urgent need for effective anti-malarial vaccines. One mechanism of malaria immunity is achieved through induction of complement-fixing antibodies. However, complement has also been associated with malarial anaemia. This thesis aims to improve our understanding of factors leading to robust induction of protective complement-fixing antibodies in malaria, as well as roles of complement in the pathogenesis of malarial anaemia. I will investigate protective and pathogenic roles of complement across age and parasite species by using clinical samples from multiple unique human cohorts.
Results – Chapter 3: Complement-fixing antibodies were prevalent during acute
Plasmodium vivax infection, with distinct antibody composition in children and adults. Importantly, both IgG and IgM were functional in fixing complement. This is the first comprehensive report investigating complement-fixing antibody induction in P. vivax malaria.
Chapter 4: The induction of complement-fixing antibodies is age-dependent, with higher induction in adults compared to children following Plasmodium falciparum malaria. Adults have high quantity and quality of circulating T-follicular helper cells (cTfH) during infection and increased cTfH activation was associated with antibody secreting B-cells.
Chapter 5: The role of complement regulatory protein (CRP) loss on red blood cells (RBCs) in malarial anaemia is independent of age and parasite species. CRPs were reduced on uninfected but not parasitised RBC during P. falciparum and P. vivax infection. Importantly, complement-fixing antibodies were not associated with malarial anaemia.
Chapter 6: Removal of CRPs occurred early in mild malarial anaemia and following a low-density infection of malaria in volunteers. Greater loss of CRPs was observed in reticulocytes compared to normocytes.
Conclusion: Together, this thesis provided significant contributions on understanding the factors that mediate functional antibody induction in malaria, including host age, parasite species, and cellular immune mechanisms. Pathogenesis of complement in malarial anaemia is also comprehensively discussed.
|Date of Award||Sep 2019|
|Supervisor||Michelle Boyle (Supervisor)|