Clinical School (Royal Melbourne Hospital) - Theses
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ItemInnate cellular responses to malaria in children and pregnant women( 2018)Malaria is one of the leading causes of morbidity and mortality in young African children and pregnant women. Clinical presentations and outcomes of P. falciparum infections are influenced by a combination of host, parasite and environmental factors. In the absence of an effective vaccine, it is important to understand how parasite and environmental factors interact with host innate immunity to influence disease severity in paediatric and pregnancy-related malaria. Aim 1, investigated the association between P. falciparum erythrocyte membrane protein 1 (PfEMP1) and inflammatory responses in clinical malaria syndromes. Malaria-infected erythrocytes (IE) were isolated from Malawian children with cerebral or uncomplicated malaria to compare their PfEMP1 profiles and cytokine elicitation capacity on malaria naïve PBMC. Also, Monocyte-derived macrophages (MDM) from Melbourne donors were exposed to isogenic parasite lines with different PfEMP1 phenotypes including (CS2: CSA binder; P6A1: CD36 binder; P6G2: CD36; E8B: CD36 and ICAM-1 binders) to determine whether PfEMP1 binding characteristics influence cytokine production. According to the var typing data of the clinical parasites from Malawi, the transcription of group A PfEMP1 was significantly higher in cerebral malaria isolates compared to the uncomplicated malaria isolates. Following in vitro stimulation of PBMC, IE from cerebral malaria isolates induced higher pro-inflammatory cytokines compared to the uncomplicated malaria isolates, suggesting a relationship between PfEMP1 expression and the elicited cytokine responses. Furthermore, MDM stimulations with CD36 binding parasites generated significantly lower inflammatory cytokines compared to the non-CD36 binding line. Together, findings of this study suggest that PfEMP1 binding phenotypes influence inflammatory responses and consequently disease severity. In Aim 2, innate cellular responses in acute and convalescence were compared between children with cerebral and uncomplicated malaria from Malawi. The objective was to evaluate the influence of inflammatory responses and monocyte subpopulations in malaria severity. Plasma levels of inflammatory cytokines and the proportion of monocyte subsets were analysed at presentation (day 0) and follow-up (day 28). Although inflammatory cytokine levels were significantly elevated during acute infection, responses were similar between cerebral and uncomplicated malaria. Consistently, monocyte profiles were not different between the two malaria groups. Aim 3, was to investigate the effects of factors such as gravidity, lifetime malaria exposure, active malaria infection and different P. falciparum strains on maternal innate immunity. PBMC from primigravidae and multigravidae pregnant women from Papua New Guinea (PNG) (with or without current infection) and Australia were stimulated with CS2-IE (CSA binder), P6A1-IE (CD36 binder) or controls (PHA & uRBC). In this study, PBMC responses were not influenced by gravidity in both study cohort or current malaria infection among PNG women. Compared to samples for Australia, PBMC from PNG produced significantly higher cytokine levels to both CS2-IE and PHA, suggesting a geography-related influence not entirely specific to malaria exposure. Between the two parasite lines, PBMC stimulations with CS2-IE elicited higher responses for some cytokines compared to P6A1-IE. These observations suggest that maternal innate immunity to malaria is influenced by geographic origin and different P. falciparum strains. The findings from these studies have added to our current understanding of P. falciparum-induced immunopathology and identified mechanisms that could be exploited for the development of new intervention strategies targeted towards innate immune modulation.