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Title: Early parasite-host interactions in controlled human malaria infection
Author: Milne, Kathryn Helen
ISNI:       0000 0004 7655 2119
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Severe malaria infections cause over 400,000 deaths annually, mostly among African children under 5 years of age. In order to reduce the burden of this disease, focus must be placed on understanding what drives pathogenesis in those at greatest risk. It is increasingly appreciated that early immune responses such as inflammation and phagocytosis, although important for host defense, can also contribute to pathogenesis when unrestrained. However, most studies of human malaria have been conducted at the terminal stages of infection, making it difficult to identify the early immune events that may be dictating clinical outcome. The expression of Plasmodium falciparum erythrocyte membrane 1 (PfEMP1), along with other variant surface antigens (VSAs), is also thought to influence disease severity, by mediating parasite-host interactions that lead to obstruction of blood flow and organ dysfunction in the non-immune host. Yet, whether these parasite proteins actually drive pathology has been difficult to assess. It is likely that a contribution of both parasite genetics and host immune responses is involved in the progression to severe disease, but how the two might interact to drive this outcome has not yet been explored. Using controlled human malaria infection (CHMI), this study aimed to: (1) characterise the early immune response to P. falciparum during primary infection and investigate inter-individual variability within the cohort, (2) assess patterns of parasite VSA expression during infection in the malaria-naïve host and (3) determine the influence of parasite VSA expression on the developing immune response, and vice versa. Microarray analysis of the host (whole blood) response to P. falciparum revealed a dichotomous pattern of gene expression, with volunteers demonstrating either up-regulation or down-regulation of genes associated with the innate inflammatory response, cell signaling and metabolism. This inter-individual variability correlated with chemokine levels in the plasma and clinical adverse events, but not with parasite growth in the circulation. RNA-sequencing of parasites, isolated from the blood of these individuals, demonstrated broad-level expression of PfEMP1-encoding var genes. However, expression was dominated by variants out-with those that have been associated with severe disease, and was remarkably similar across samples from all volunteers despite the observed diversity in host responses. Although we cannot speculate as to the severity of outcome in the volunteers, these findings challenge some key concepts in the field, for instance: (1) expression of group-A (disease associated) PfEMP1 is not driving, nor is required for early disease outcome in malaria-naïve individuals and (2) the host immune response is not directed by parasite gene expression, and vice versa; the type of host immune response elicited has little influence of parasite VSA expression early in infection. Focus should now be placed on understanding the diversity of host immune responses produced during primary P. falciparum infection, the clinical outcome(s) associated with these responses and the host genetic/environmental factors that may serve to protect against severe malaria disease.
Supervisor: Spence, Philip ; Rowe, Alex Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Plasmodium falciparum parasite ; malaria ; B/A proteins ; host immune system ; early immune events ; disease severity ; diversity