Cell biological analysis reveals an essential role for Pfcerli2 in erythrocyte invasion by malaria parasites

Benjamin Liffner,Ella May Edwards,Gerald J Shami,Sonja Frölich,Jan Strauss,Danny W Wilson,Tim-Wolf Gilberger,Juan Miguel Balbin,Leann Tilley,Gary K Heinemann,Jan Stephan Wichers,Arne Alder,Ghizal Siddiqui,Darren J Creek,Matthew W A Dixon

doi:10.1038/s42003-022-03020-9

Abstract

Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Here we characterise P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 2 (PfCERLI2), as a rhoptry bulb protein that is essential for merozoite invasion. Phylogenetic analyses show that cerli2 arose through an ancestral gene duplication of cerli1. We show that PfCERLI2 is essential for blood-stage growth and localises to the cytosolic face of the rhoptry bulb. Inducible knockdown of PfCERLI2 led to a proportion of merozoites failing to invade and was associated with elongation of the rhoptry organelle during merozoite development and inhibition of rhoptry antigen processing. These findings identify PfCERLI2 as a protein that has key roles in rhoptry biology during merozoite invasion.

Highlights

Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum
PfCERLI1 and PfCERLI2 both possess a C2 domain towards their N-terminus as well as a short but highly conserved motif we have termed PHIS, which has the consensus sequence PHIS[-]xxP ([-] = negatively charged) in P. falciparum
We and Suarez et al had previously characterised the rhoptry bulb protein PfCERLI1 and determined that it played an essential role in merozoite invasion and rhoptry secretion[13,14]

Summary

Introduction

Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Inducible knockdown of PfCERLI2 led to a proportion of merozoites failing to invade and was associated with elongation of the rhoptry organelle during merozoite development and inhibition of rhoptry antigen processing. During the process of RBC invasion, the neck of the rhoptries fuse to the parasite plasma membrane (PPM) to allow secretion of rhoptry contents[9]. We describe PfCERLI2 (Pf3D7_0405200), a paralogue of Pfcerli[1], which localises to the cytosolic face of the rhoptry bulb membrane and is essential for merozoite invasion of RBCs

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