Abstract
Red blood cell (RBC) invasion by malaria merozoites involves formation of a parasitophorous vacuole into which the parasite moves. The vacuole membrane seals and pinches off behind the parasite through an unknown mechanism, enclosing the parasite within the RBC. During invasion, several parasite surface proteins are shed by a membrane-bound protease called SUB2. Here we show that genetic depletion of SUB2 abolishes shedding of a range of parasite proteins, identifying previously unrecognized SUB2 substrates. Interaction of SUB2-null merozoites with RBCs leads to either abortive invasion with rapid RBC lysis, or successful entry but developmental arrest. Selective failure to shed the most abundant SUB2 substrate, MSP1, reduces intracellular replication, whilst conditional ablation of the substrate AMA1 produces host RBC lysis. We conclude that SUB2 activity is critical for host RBC membrane sealing following parasite internalisation and for correct functioning of merozoite surface proteins.
Highlights
The phylum Apicomplexa comprises a diverse group of protozoan organisms, many of which are obligate intracellular parasites of clinical or veterinary importance
We show that SUB2 depletion results in defects in merozoite surface protein shedding and sealing of the host Red blood cell (RBC) upon invasion, leading to either abortive invasion with loss of host RBC haemoglobin, or developmental arrest of the intracellular parasite
Our primary mechanistic explanation for this is that shedding is required for resealing of the RBC membrane at invasion (Figure 8)
Summary
The phylum Apicomplexa comprises a diverse group of protozoan organisms, many of which are obligate intracellular parasites of clinical or veterinary importance. A feature of these parasites is their possession of invasive forms that actively penetrate host cells. Invasion ends with sealing of the RBC behind the intracellular parasite, concomitant with pinching off of the nascent PV membrane (PVM) in a membrane scission event such that the PVM is eventually non-contiguous with and internal to the RBC membrane. Whilst many advances have been made over recent decades in understanding invasion, in the most lethal malaria species Plasmodium falciparum and Plasmodium knowlesi, as well as in the related apicomplexan parasite Toxoplasma gondii, the mechanisms underlying PV formation
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