Complex roles ankyrin-1 plays in malaria infections

Abstract

Despite the numerous interventions employed in the past few decades, malaria remains one of the most lethal diseases affecting millions of people worldwide. This is partly due to the emergence of resistance to the current parasite-targeted antimalarials. In contrast, erythrocytic genetic mutations have been conferring malaria protection in humans for thousands of years without losing their effectiveness. This presents a new therapeutic approach to mimic these genetic mutations to treat malaria, known as host-directed therapy (HDT), which requires further understanding of host-parasite interactions to identify potential HDT drug targets. One such HDT target is the erythrocytic cytoskeleton, which parasites rely on for their survival. Ankyrin-1 (Ank-1) is one of erythrocytic cytoskeleton proteins, which has been associated with hereditary spherocytosis (HS) in humans. This thesis investigates the roles of Ank-1 in malaria infections using mouse models and blood from HS patients. Mice with Ank-1 mutations were found to exhibit phenotypes similar to human HS patients and are protected against malaria via multiple mechanisms, suggesting that Ank-1 plays a complex role in malaria infections. These mechanisms are heavily influenced by the nature of Ank-1 mutations, which is further confirmed in human HS erythrocytes. This thesis also explores the possibility of using the ankyrin-spectrin interaction as a HDT target. Results show that the disruption of this interaction has little effect on the health of the mice, while conferring significant resistance towards malaria, thus enabling the use of high throughput screening (HTS) for drug discovery. To summarise, this thesis highlights the complex interactions between the erythrocyte cytoskeleton and malarial parasites, as well as providing insights into the heterogeneous protective role of Ank-1 in mediating malaria resistance. It also raises the possibility of using erythrocytic cytoskeletal proteins as HDT drug targets, which could potentially yield novel therapies for malaria in the future.