Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites

Area of Science:

• Malariology
• Parasitology
• Molecular Biology

Background:

• Red blood cell (RBC) invasion by Plasmodium merozoites is essential for malaria parasite survival.
• Duffy binding-like proteins (DBPs) and reticulocyte binding-like proteins (RBLs) are key mediators of RBC invasion in Plasmodium species.
• Plasmodium knowlesi, a zoonotic malaria parasite, possesses a streamlined repertoire of invasion proteins compared to Plasmodium falciparum.

Purpose of the Study:

• To elucidate the precise roles and sequential order of key invasion events mediated by DBPs and RBLs in Plasmodium knowlesi.
• To investigate the distinct functions of DBPα and NBPXa in the invasion of human RBCs by P. knowlesi.
• To explore potential synergistic therapeutic targets for malaria invasion inhibitors.

Main Methods:

• Utilized iterative CRISPR-Cas9 genome editing in Plasmodium knowlesi.
• Leveraged the unique biological characteristics of P. knowlesi for invasion studies.
• Determined the temporal sequence of critical host cell invasion milestones.

Main Results:

• Demonstrated distinct functional roles for the DBP and RBL protein families in P. knowlesi invasion.
• Established the essentiality of DBPα and NBPXa for human RBC invasion by P. knowlesi.
• Identified a phased commitment mechanism underlying merozoite invasion.

Conclusions:

• The distinct roles of P. knowlesi DBPs and RBLs support a model of phased invasion commitment.
• This phased mechanism presents a viable target for synergistic inhibition by antibodies.
• Understanding these distinct roles is crucial for developing novel anti-malarial strategies.