Shedding of host autophagic proteins from the parasitophorous vacuolar membrane of Plasmodium berghei

Abstract

The hepatic stage of the malaria parasite Plasmodium is accompanied by an autophagy-mediated host response directly targeting the parasitophorous vacuolar membrane (PVM) harbouring the parasite. Removal of the PVM-associated autophagic proteins such as ubiquitin, p62, and LC3 correlates with parasite survival. Yet, it is unclear how Plasmodium avoids the deleterious effects of selective autophagy. Here we show that parasites trap host autophagic factors in the tubovesicular network (TVN), an expansion of the PVM into the host cytoplasm. In proliferating parasites, PVM-associated LC3 becomes immediately redirected into the TVN, where it accumulates distally from the parasite’s replicative centre. Finally, the host factors are shed as vesicles into the host cytoplasm. This strategy may enable the parasite to balance the benefits of the enhanced host catabolic activity with the risk of being eliminated by the cell’s cytosolic immune defence.

Identification of Plasmodium falciparum proteoforms from liver stage models

“…After sporozoites enter the hepatocyte cytoplasm, they form a parasite vacuolar membrane that interfaces with the host autophagy system [35][36][37]. Parasites have designed a system to escape this endogenous cytoplasmic immunity that involves disrupting autophagy and lysosome interactions with the parasitophorous vacuole membrane (PVM) [38].…”

“…Parasites have designed a system to escape this endogenous cytoplasmic immunity that involves disrupting autophagy and lysosome interactions with the parasitophorous vacuole membrane (PVM) [38]. Specifically, the parasite tubovesicular network can sequester host factors that damage the PVM [37]. Liver stage schizonts that increase in size and ultimately succeed in the developmental process do not have autophagy and lysosomal markers associated with the PVM [37].…”

“…Specifically, the parasite tubovesicular network can sequester host factors that damage the PVM [37]. Liver stage schizonts that increase in size and ultimately succeed in the developmental process do not have autophagy and lysosomal markers associated with the PVM [37]. These past studies suggest that the parasite has evolved mechanisms to evade degradation by the host cytoplasmic immune response.…”

Intravital imaging of host‐parasite interactions in organs of the thoracic and abdominopelvic cavities

“…Components of the host autophagy machinery such as LC3 (green) recognise and decorate the parasite's parasitophorous vacuole membrane (PVM) (red) from early on in infection (Scale bar, 10 μm) (Image adapted from Prado et al, ). (iii) Parasites that escape the autophagy‐associated response control the amount of PVM‐associated LC3 during development (Scale bar, 10 μm) (Image adapted from Agop‐Nersesian et al, ). (iv) IVM has allowed visualisation of organelle fission during schizogony, such as the endoplasmic reticulum (Pb Sec61b shown in white) at sub‐cellular resolution (Scale bar, 10 μm) (Image adapted from Kaiser et al, ).…”

“…The same parasite death phenotypes were also observed independent of cell‐mediated immune responses under cell culture conditions (Eickel et al, ). Observed by in vitro imaging as well as IVM, dying liver schizonts were classified in three morphologically distinct types of parasite deaths (a) apoptosis‐like, (b) necrosis‐like and (c) autophagy‐like programmed cell death (Agop‐Nersesian et al, ; Cockburn et al, ; Eickel et al, ). Parasite development can be restricted by intra‐cellular defence mechanisms.…”