Medical Biology - Theses
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ItemLow birthweight and infant growth among children in Papua New Guinea - effect of malaria and other infectious diseases during childhood( 2020)Globally, young children continue to die or fail to thrive from treatable and preventable causes including low birthweight (LBW), childhood undernutrition (wasting, stunting, underweight) and infectious diseases. Reducing the burden of these are an essential pillar of global child health and survival targets. These global trends are reflected in Papua New Guinea (PNG), a resource constrained setting that continues to observe high rates of illness and death in young children with LBW, childhood undernutrition and infectious diseases (especially malaria, pneumonia and diarrhoea) continuing to be the leading causes. Improving child health and survival in PNG requires evidence about the risk factors for LBW, sub-optimal growth and infectious diseases, as well as the inter-relatedness of risk factors, that can inform policies and identify appropriate interventions and strategies. This thesis aims to address critical knowledge gaps in this area and provide insights to inform interventions and strategies aimed at reducing low birthweight, childhood undernutrition and malaria in young children in PNG and globally. LBW is caused by a multitude of factors which are often inter-related and with that, it is often difficult to distinguish between independently direct and indirect effects. Moreover, current interventions targeted at preventing LBW generally assume a single dominant cause overlooking the inter-relatedness of risk factors and the possibility of factors exerting joint effects on LBW. These are difficult to establish with widely used standard statistical methods and have therefore been rarely investigated. Using structural equation modelling, we showed intermittent preventive treatment of malaria during pregnancy with sulphadoxine-pyrimethamine (SP) plus azithromycin (AZ) to be independently directly associated with reduced probability of LBW. Unexpectedly, anaemia at enrolment was also directly associated with reduced probability of LBW. Maternal undernutrition at enrolment was independently directly associated with increased probability of LBW. No significant indirect associations between risk factors and LBW were established. After birth, children in lowlands PNG experience high rates of malaria, pneumonia and diarrhoea alongside undernutrition. Infections and undernutrition are believed to have a bi-directional relationship and whilst the effect of undernutrition on risks of illness and death is well known, little is known about the effects of malaria, pneumonia and diarrhoea on growth faltering, particularly among PNG children. By using multivariable regression and distributed lag models for data analysis, we observed malaria pneumonia and diarrhoea to have a differential impact on child growth. The effect of acute malaria on child growth was observed to be long-term while pneumonia and diarrhoea had short-term effects lasting up to 3 months. Of these three diseases, malaria was once ranked the top leading infectious cause of childhood morbidities and mortality in PNG, especially in lowlands PNG. The nationwide scale-up of malaria control interventions significantly reduced overall malaria transmission between 2008 and 2014 but a detailed understanding of the impact of this changing transmission on the epidemiology and risk profile of malaria infections and disease due to the two main species in young children was lacking. By analysing three consecutive longitudinal child cohorts (1-5-year-old children) conducted over the period of improved control (2013), we observed a differential impact of improved control on P. falciparum and P. vivax. Additionally, we showed that with declining malaria transmission, burden of malaria infections and illness were highly spatially localised to areas that had the highest burden prior to scale-up, highlighting potential hotspots of transmission. Collectively, the findings from this thesis provide important insights for improving child health in PNG and globally.
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ItemHost-Parasite Interactions in the Pathogenesis of Severe Plasmodium falciparum Malaria( 2020)Severe Plasmodium falciparum malaria has been attributed to cytoadhesion and sequestration of infected erythrocytes (IEs) to microvascular endothelium, and rosetting of IEs with other non-infected erythrocytes. These mechanisms are mediated by the interaction between variant surface antigens (VSAs) on the IEs and host receptors on the endothelial cells and erythrocytes. There are at least three VSAs important for this process, which are P. falciparum Erythrocyte Membrane Protein-1 (PfEMP-1), Repeat Interspersed Family protein (RIFIN), and Subtelomeric Variant Open Reading Frame (STEVOR). This study aimed to investigate whether the polymorphisms in the host genome that encode VSA receptors may influence the pathogenesis and mediate protection against severe malaria. Secondly, as PfEMP1, RIFIN, and STEVOR have been shown to mediate rosetting, the potential co-expression among these three VSAs were investigated by comparing their expression on the erythrocytes infected by rosetting and non-rosetting P. falciparum parasites in two different host environments based on ABO blood types (A+ vs O+ erythrocytes). Thirdly, the development of antibody against rosetting-mediating VSAs were screened in longitudinal cohort children from Papua New Guinea, and determined whether they were associated with protection against severe malaria. For the host genetic aspects, this study focused on investigating the role of the polymorphisms on the Endothelial Protein C Receptor (EPCR) encoding PROCR gene and the ABO blood types, which were shown to be associated with severe malaria, in determining the protection against severe malaria in a cohort of very young children from Papua New Guinea (PNG). In children with the PROCR rs867186 polymorphism, there was a risk-reduction trend for severe malaria incidence but it was not significant which was likely due to small number severe malaria cases (n=24). However, the ABO blood group was not found to be associated with protection against severe and clinical malaria. In addition, the significantly higher levels of antibodies to rosetting-associated than EPCR binding PfEMP-1-CIDR domains in children carrying the PROCR polymorphism suggested the preference towards parasites expressing non-EPCR binding VSAs, such as rosetting mediating VSAs. The in vitro cultures for rosetting parasites in A+ and O+ erythrocytes showed distinct patterns of upregulated genes where more VSAs consisting mainly PfEMP-1 and RIFIN were seen in A+ than O+ rosetting parasites, and consequently a higher rosetting rate in the former. This is consistent with previous studies showing that individuals with O blood type tended to have low rosetting rate and were protected from severe malaria. The antibody detection using the sera from the PNG cohort children against rosetting associated RIFIN and STEVOR identified in this study showed a consistent pattern indicating the role of ABO blood group as well as the PROCR polymorphism in determining the selection of VSA subtypes. In conclusion, this study is the first to link host genetic polymorphisms with differential exposure to malaria antigens and highlights the importance of considering the diverse environment in which natural infections occur. This study has provided a better insight into the complex host-parasite interactions during P. falciparum pathogenesis, which is crucial to form a basis to further develop the most effective approach to interrupt this process. Future studies are mainly directed to validate the findings using a study population with more severe disease cases and higher level of immunity, as well as replicating the in vitro rosetting study in different parasite isolates to confirm whether VSA expression is conserved across different P. falciparum rosetting parasite strains.
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ItemMerozoite antigens of Plasmodium falciparum elicit strain transcending opsonising immunity( 2015)Despite progress towards reducing the global burden, malaria continues to cause approximately 200 million cases and 600,000 deaths annually (World Health Organization, 2014). Although several malaria vaccines are currently in clinical trials, no advanced vaccine candidate has yet demonstrated sufficient efficacy to be a stand-alone vaccine against the highly variant Plasmodium falciparum parasite. Development of effective vaccine strategies requires knowledge of the essential mechanisms for protective immunity and robust assays to serve as correlates of protective immunity. However, exactly which antibody functions are necessary to control parasitemia and clinical symptoms during natural infection remains unclear. The merozoite represents an attractive vaccine target, as antibodies to numerous merozoite antigens have been associated with protective immunity in human cohort studies. This thesis aimed to investigate the importance of merozoite opsonising antibodies for immunity to malaria. Opsonising antibodies, and the Fc Receptor-mediated functions these antibodies elicit, have been poorly studied in malaria partly due to limitations of in vitro assays. Therefore, in this thesis a merozoite phagocytosis assay was developed and validated (Chapter 3), and robust and reproducible phagocytosis responses from THP-1 cells were observed. This assay was then used to measure merozoite opsonisation in a longitudinal study of semi-children from Papua New Guinea (PNG), and phagocytosis responses were demonstrated to correlate with protection from clinical disease and high-density parasitemia (Chapter 4). Due to the highly diverse nature of P. falciparum merozoites, it was important to assess whether merozoite opsonisation involved strain-specific or strain-transcending specificities (Chapter 5). Highly consistent opsonisation and associations with immunity were observed across a panel of common laboratory strains and PNG parasites adapted to growth in vitro. Through use of transgenic parasite lines, the absence of MSP3, MSP6, MSPDBL1 or MSP1-19 was not observed to impact the overall level of merozoite phagocytosis. By depleting antibody reactivity to 3D7 merozoites, opsonisation of merozoites from PNG strains also declined, suggestive of conserved antigenic targets across parasite strains. The findings in this thesis have demonstrated the importance of opsonising antibodies and their associated phagocytic responses for protective immunity to malaria. Robust, reproducible and well-validated assays are a priority to aid pre-clinical and clinical malaria vaccine development. The consistent responses and protective associations provide strong support for merozoite opsonisation as a robust correlate of protective immunity in malaria endemic populations. As the majority of merozoite opsonising antibodies were strain-transcending, uncovering these conserved domains within merozoite surface antigens may yield important novel vaccine candidates with which to tackle this deadly disease.