Plasmodium falciparum exoerythrocytic forms require the PTEX translocon for development in human hepatocytes
2023•researchsquare.com
Plasmodium falciparum assembles a protein translocon (PTEX) at the parasitophorous
vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins
are exported. The preceding Plasmodium liver stage develops in hepatocytes within a PVM;
however, the importance of PTEX and identification of exported proteins in P. falciparum
liver stages remains unexplored. Here, we apply the FlpL/FRT system to P. falciparum NF54
to conditionally excise genes in sporozoites, enabling studies at the liver stage. Conditional …
vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins
are exported. The preceding Plasmodium liver stage develops in hepatocytes within a PVM;
however, the importance of PTEX and identification of exported proteins in P. falciparum
liver stages remains unexplored. Here, we apply the FlpL/FRT system to P. falciparum NF54
to conditionally excise genes in sporozoites, enabling studies at the liver stage. Conditional …
Abstract
Plasmodium falciparum assembles a protein translocon (PTEX) at the parasitophorous vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins are exported. The preceding Plasmodium liver stage develops in hepatocytes within a PVM; however, the importance of PTEX and identification of exported proteins in P. falciparum liver stages remains unexplored. Here, we apply the FlpL/FRT system to P. falciparum NF54 to conditionally excise genes in sporozoites, enabling studies at the liver stage. Conditional disruption of PTEX components PTEX150 and EXP2 in sporozoites does not affect their development or infectivity but attenuates liver stage growth. While PTEX150-deficiency significantly reduces liver load in humanized mice, EXP2-deficiency conferred a severe fitness cost, demonstrating that PTEX is essential for P. falciparum liver stage development. We show that liver specific protein 2 (LISP2) and circumsporozoite protein (CSP) contain putative PEXEL sequences cleaved by plasmepsin V, yet they localize to the PVM of infected hepatocytes. The abundance of LISP2 is reduced in PTEX-deficient liver stages, suggesting this protein is degraded in the absence of a functioning PTEX complex. This study employs the FlpL/FRT system for functional analysis of P. falciparum pre-erythrocytic biology, revealing that the protein export translocon required for growth in erythrocytes is essential for P. falciparum development in hepatocytes and normal LISP2 expression. It also describes two P. falciparum proteins that contain putative PEXEL motifs that are targeted to the PVM.
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