An Analysis Of The Immunoglobulin Gene Repertoire In The Human B Cell Response To Plasmodium falciparum During Natural And Experimental Malaria Infections

Mutai, Jacqueline (2023). An Analysis Of The Immunoglobulin Gene Repertoire In The Human B Cell Response To Plasmodium falciparum During Natural And Experimental Malaria Infections. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00015d55

Abstract

B cells are important in immunity to the malaria parasite Plasmodium falciparum (P. falciparum). Effective responses rely on generating diverse P. falciparum antigen-specific B cell receptors (BCR) through somatic genetic rearrangements. BCR sequencing has previously been used to characterise the diversity of the BCR repertoire before and after infection, but not to understanding how clinical immunity to P. falciparum infection develops. Understanding this relationship could inform the development of more effective vaccines.

I explored the development of B cell responses in two sample sets: Kenyan children exposed to natural malaria infection and Kenyan adults from a Controlled Human Malaria infection study (CHMI) who were either febrile or parasite negative after infection. B-cells were immunophenotyped to characterise the dynamic nature of B-cell responses longitudinally, and RNA was extracted for BCR sequencing.

In the CHMI samples, individuals who developed fever did not increase their overall B-cell levels over time but had higher frequencies of classical memory B cells (MBCs) and plasmablasts post-infection than parasite negative individuals. By contrast, parasite negative individuals had higher frequencies of activated and atypical MBCs. There was no increase in any B cell subsets across time in children, although in younger children plasmablasts increased during Pf infection.

The global BCR repertoire was similar between adults and children, both in the heavy chain V and J genes used and the length of the complementary-determining region 3, but B cell clones were largely unique to each sample groups. Diversity measures in the IgG isotype were lower in febrile individuals compared to parasite negative. In the IgM isotype there was lower diversity during malaria in children compared to the adults, indicating a switch to the IgG isotype with age. These observations suggest that the underlying germline shapes the overall B cell repertoire, but Pf infection dominates diversity of clones in children and adults.