PTRAMP, CSS and Ripr form a conserved complex required for merozoite invasion of Plasmodium species into erythrocytes

Area of Science:

• Parasitology
• Structural Biology
• Immunology

Background:

• Erythrocyte invasion by Plasmodium is crucial for malaria pathogenesis.
• The Plasmodium falciparum Rh5-containing PCRCR complex binds erythrocyte basigin, mediating invasion.
• Orthologs of PTRAMP, CSS, and Ripr are conserved across the Plasmodium genus, unlike Rh5.

Purpose of the Study:

• To investigate conserved features of the PTRAMP, CSS, and Ripr complex across different Plasmodium species.
• To understand the structural basis of the Plasmodium genus (PCR) complex.
• To explore the potential of the PCR complex as a target for multi-species malaria vaccines.

Main Methods:

• Comparative analysis of PTRAMP, CSS, and Ripr orthologs from P. vivax and P. knowlesi.
• Biochemical assays to confirm heterodimerization and complex formation.
• Cryo-electron microscopy (Cryo-EM) to visualize the P. knowlesi PCR complex structure.
• Antibody-based invasion inhibition assays.

Main Results:

• PTRAMP and CSS form a disulfide-linked heterodimer in P. vivax and P. knowlesi, similar to P. falciparum.
• The PCR complex in these species binds Ripr via its C-terminal region.
• Cryo-EM revealed a conserved invasion scaffold within the Plasmodium PCR complex.
• Cross-reactive antibodies targeting the PCR complex showed differential inhibition of merozoite invasion.

Conclusions:

• The PCR complex represents a conserved invasion scaffold across Plasmodium species.
• Structural insights into the PCR complex provide a foundation for developing pan-Plasmodium malaria vaccines.
• Targeting the conserved PCR complex holds promise for broad-spectrum malaria control.