In Vivo Function of PTEX88 in Malaria Parasite Sequestration and Virulence

Abstract

e Malaria pathology is linked to remodeling of red blood cells by eukaryotic Plasmodium parasites. Central to host cell refurbishment is the trafficking of parasite-encoded virulence factors through the Plasmodium translocon of exported proteins (PTEX). Much of our understanding of its function is based on experimental work with cultured Plasmodium falciparum, yet direct consequences of PTEX impairment during an infection remain poorly defined. Using the murine malaria model parasite Plasmodium berghei, it is shown here that efficient sequestration to the pulmonary, adipose, and brain tissue vasculature is dependent on the PTEX components thioredoxin 2 (TRX2) and PTEX88. While TRX2-deficient parasites remain virulent, PTEX88-deficient parasites no longer sequester in the brain, correlating with abolishment of cerebral complications in infected mice. However, an apparent trade-off for virulence attenuation was spleen enlargement, which correlates with a strongly reduced schizont-to-ringstage transition. Strikingly, general protein export is unaffected in PTEX88-deficient mutants that mature normally in vitro. Thus, PTEX88 is pivotal for tissue sequestration in vivo, parasite virulence, and preventing exacerbation of spleen pathology, but these functions do not correlate with general protein export to the host erythrocyte. The presented data suggest that the protein export machinery of Plasmodium parasites and their underlying mechanistic features are considerably more complex than previously anticipated and indicate challenges for targeted intervention strategies.

Critical Steps in Protein Export of Plasmodium falciparum Blood Stages

“…This might be required in the oxidising environment of the PV [59,60]. HSP101 and PTEX150 are both suspected to be present as oligomers [52,55] and are mandatory for PTEX function, whereas TRX2 and PTEX88 have less central roles [55,[61][62][63] and are present in lower stoichiometries [56]. Notably, protein export in PTEX88-deficient Plasmodium berghei parasites was not measurably decreased but sequestration in infected mice was reduced by an unknown mechanism [62].…”

Spatial organization of protein export in malaria parasite blood stages

“…All 3 of these proteins are essential for the survival of Plasmodium parasites . TRX2 and PTEX88 are not essential for survival of the rodent malaria parasite Plasmodium berghei, but are important for efficient protein export and potentially serve auxillary functions such as recognition of protein cargo subsets . Additional PTEX associated proteins have recently been identified including Pf113, and the exported chaperone HSP70‐x .…”

Targeted Deletion of a Plasmodium Site-2 Protease Impairs Life Cycle Progression in the Mammalian Host

“…In the murine malaria model functional assays for schizogony are limited, since P . berghei schizonts do not rupture in vitro , while in vivo they get sequestered to the spleen and the liver [49]. …”