Investigating the effect of Plasmodium falciparum infected red blood cells on dendritic cell function

Osii, Rowland Sadia (2022) Investigating the effect of Plasmodium falciparum infected red blood cells on dendritic cell function. PhD thesis, University of Glasgow.

Abstract

Malaria remains a global health problem, that affects majority of the world’s population living in tropical and subtropical areas of the world. Its impact, in terms of morbidity and mortality is highest in sub-Saharan Africa, and especially among children under the age of 5. While the intensive application of currently available malaria control tools has greatly reduced malaria transmission, the possibility of malaria elimination remains a distant goal. Thus, novel innovative methods are required to complement the existing control tools to push malaria further towards elimination. Vaccine induced immunity is one of the most cost-effective methods for controlling infectious diseases and has led to the elimination of some. Encouragingly, residents of highly endemic regions develop naturally acquired immunity that offers protection against clinical symptoms of malaria. However, naturally acquired immunity is incomplete as its permissive of asymptomatic infections and develops slowly after several rounds of repeated infections. This slow development of immunity may be attributed to the ability of the parasite to modify dendritic cell function, though neither the mechanisms of this alteration, nor its impact on the downstream cellular and antibody host responses are well understood. A better understanding of the basic biology of the interactions of malaria parasites with the human host is therefore, clearly warranted, and will be instrumental in the design and development of highly effective vaccines.
To investigate the cellular and molecular pathways underpinning the alteration of dendritic cell function upon exposure to parasite infected red blood cells (iRBC), I established an in vitro assay using monocyte-derived dendritic cells from adults, irrespective of prior exposure to malaria. Exposure of dendritic cells to iRBCs did not result in activation. However, when the iRBC-exposed dendritic cells were subsequently stimulated with lipopolysaccharide (LPS), they were unable to express key co-stimulatory molecules to the same extent as LPS stimulated control RBC exposed dendritic cells. Nonetheless, these iRBC treated dendritic cells were still capable of inducing upregulation of the early activation marker, CD69, in CD4 T cells in a mixed lymphocyte reaction. Single cell RNA sequencing of cells from the mixed lymphocyte reaction between iRBC pre-treated dendritic cells and CD4 T cells initiated transforming growth factor beta driven signalling that altered dendritic cell function, resulting in expansion of the CD4 T regulatory cells.
Having delineated the molecular pathways elicited by the iRBC treatment of dendritic cell function in vitro, I wanted to see whether I would observe similar changes in cellular function in vivo. I took advantage of samples from a medical experiment involving a controlled human malaria infection (CHMI) study at the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya. The participants in this study were recruited from malaria endemic areas with varying levels of P. falciparum transmission intensity. Specifically, I compared changes in gene expression with CHMI between two groups using longitudinal samples: those that developed a productive infection with no symptoms (“chronic”) and those that became infected and developed fever (“febrile”). Monocytes from the chronic participants exhibited an early production of type II interferon, while monocyte from the febrile participants upregulated type 1 interferons. Interestingly, type II interferons are thought to be involved in immune control of malaria infections, while type I interferons can hamper the establishment of an adequate immune response.
The work presented herein provides insight into the signalling pathways that are activated by dendritic cells and monocytes upon their interaction with iRBCs, and how adults recruited from malaria endemic area (grouped into febrile and chronic participants) can have varying abilities to control infection based on the type of the immune response induced following CHMI.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Brewer, Prof. James, Garside, Prof. Paul and Ndungu, Prof. Francis
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-83117
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 09 Sep 2022 12:12
• Last Modified: 09 Sep 2022 12:14
• Thesis DOI: 10.5525/gla.thesis.83117
• URI: https://theses.gla.ac.uk/id/eprint/83117