Dissecting the role of host receptor context and cytoskeletal disruption in malaria parasite invasion

Using novel reticulocyte phenotypes derived through in vitro erythroid culture that comprise both domain swap hybrid surface receptor proteins and modified cytoskeletal adaptor proteins we will explore the role of host proteins in this process at both the extracellular and intracellular face of the membrane.

Whilst essential roles for several RBC membrane proteins have recently been reported, in many cases insight into the role that these host cell proteins actually play in the invasion process, extending beyond mere putative sites of attachment is severely or completely lacking. In vitro derived reticulocytes in which customised mutant and domain swap hybrid receptors basigin, CD55 and CD44 are expressed upon knockout backgrounds will enable us to determine the requirement for specific plasma membrane context, associations and mobility of these host receptors for successful invasion.

Since extracellular attachment of the merozoite to the RBC potentiates the transient cytoskeletal disruption required for invasion we will also investigate the basis of this host remodelling event. Using site specific editing of phospho-modifiable residues on adducin and other proteins we will uncover the role of cytoskeletal adaptor associations and their regulation within the host junctional complex. Through interrogation of both the invasive susceptibility and biomechanical properties of these modified cells we will determine the nature of and degree to which existing host mechanisms for regulating cell deformability are co-opted or circumvented by the parasite and identify potential approaches to target invasion without impaired capillary deformation capacity.

Project details

Enabling Technologies & Assays

Aug 2021 — Aug 2024

$804,523

United Kingdom