Harris, Lynne Mary

2018-09-13T15:59:37Z

2018-09-13T15:59:37Z

2013

In hyperendemic malarious regions adults develop protective immunity to Plasmodium falciparum infection. In order for this immunity to develop the host immune system must be able to recognise the parasite. One stage at which this occurs is prior to red blood cell invasion when the extracellular form of the parasite, the merozoite, presents the host immune system with a number of potential immunogens termed merozoite surface antigens. Antibodies to merozoite surface antigens are able to inhibit the growth and development of the parasite in vitro. This thesis explores the mechanisms by which merozoite surface antigen -specific antibodies exert this inhibition.

The affinity, fine specificity and Fc- mediated effects of antibodies may affect their functional activity. Immortalised B cell lines producing merozoite surface antigen - specific human monoclonal antibodies were generated in order to investigate the effect of these factors on their growth inhibitory activity in vitro. The preliminary characterisation of these mAbs is described in chapter 3. However, sufficient quantities of these mAbs could not be generated for their functional activity to be investigated in vitro.

Current dogma holds that the primary function of antibodies is to provide a molecular link between antigen recognition and pathogen destruction. However, all Abs have the ability to catalyse a reaction between singlet oxygen and water to generate hydrogen peroxide. This thesis explored the hypothesis that this antibody-catalysed water-oxidation pathway is responsible for the intraerythrocytic growth inhibition exerted by MSP-1-₁₉-specific Abs. An in vitro ACWO assay was developed to test this hypothesis and data suggest that ACWO may occur in infected RBCs associated with an anti- MSP-1-₁₉ monoclonal antibody.

Antibodies specific to an intrinsically unstructured region from the C- terminal half of merozoite surface protein 3.3, designated MSP3.3C, are highly effective at inhibiting iii the in vitro growth of P. falciparum. This thesis explored the mechanisms responsible for this inhibition. This inhibition is caused by inhibition of the intraerythrocytic development of the parasite and not by inhibition of merozoite invasion. MSP3.3C specific Abs can access the intraerythrocytic parasite post invasion and completely arrest parasite development by inducing parasite death.

The findings presented in this thesis expand current knowledge of the mechanisms by which MSA- specific Abs inhibit the growth of P. falciparum in vitro. This may prove informative both in terms of our understanding of naturally acquired antibody mediated immunity to P. falciparum asexual stages and in furthering effective vaccine design against this deadly pathogen.

http://hdl.handle.net/1842/32389

The University of Edinburgh

Annexe Thesis Digitisation Project 2018 Block 20

How merozoite surface antigen-specific antibodies inhibit Plasmodium falciparum growth in vitro

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy