Human antibody-mediated immunity against infection and parasite fecundity in Schistosoma mansoni and Schistosoma haematobium infection

Abstract

Through a combination of epidemiological and proteomic methods, the aim of this thesis was to advance understanding of antibody-driven immune responses that partially protect against infection and reduce fecundity in human schistosome infections. The relative contribution of exposure to infection and IgE antibody responses against schistosomes were explored using a mathematical modelling approach. Age intensity and serology profiles of sub-cohorts were reproduced to good approximation by incorporating explicitly defined exposure and immunity functions, fitted to field data, into an age- and sex-structured S. mansoni transmission model. However, the inferior model fit for males from one tribal group highlights the need to capture heterogeneity in antibody responses that occur with varying cumulative exposure of different demographic groups. The progressive development of protective immunity against S. mansoni infection is associated with cross-reactivity between members of the Tegument Allergen-Like (TAL) protein family. This relationship was explored further and evidence for involvement of an additional TAL family member in the development of IgE-mediated anti-infection immunity found. Evidence supporting similar cross-reactive relationships between S. haematobium TAL proteins is provided. In addition to anti-infection immunity, S. haematobium is thought subject to an anti-fecundity immune response. It is proposed that IgG1 antibodies raised to proteins within whole worm extract are responsible. A proteomic approach used to identify targets of the IgG1 returned 191 proteins, several of which are closely associated with the parasite-host interface. Three were successfully expressed and analysis identified possible associations between target specific IgG1 and reduced worm fecundity, although this was strongly confounded by host age and village of residence, a proxy for the force of transmission. These findings all demonstrate associations between the development of protective antibody responses and variations in exposure behaviour, host age or the force of transmission; the combined contribution of which will determine the level of exposure to immunostimulatory antigens and ultimately development of immunity.