Autophagy Pathways in the Genesis of Plasmodium-Derived Microvesicles: A Double-Edged Sword?

Abstract

Malaria, caused by Plasmodium species (spp.), is a deadly parasitic disease that results in approximately 400,000 deaths per year globally. Autophagy pathways play a fundamental role in the developmental stages of the parasite within the mammalian host. They are also involved in the production of Plasmodium-derived extracellular vesicles (EVs), which play an important role in the infection process, either by providing nutrients for parasite growth or by contributing to the immunopathophysiology of the disease. For example, during the hepatic stage, Plasmodium-derived EVs contribute to parasite virulence by modulating the host immune response. EVs help in evading the different autophagy mechanisms deployed by the host for parasite clearance. During cerebral malaria, on the other hand, parasite-derived EVs promote an astrocyte-mediated inflammatory response, through the induction of a non-conventional host autophagy pathway. In this review, we will discuss the cross-talk between Plasmodium-derived microvesicles and autophagy, and how it influences the outcome of infection.

Oleuropein activates autophagy to circumvent anti-plasmodial defense

“…This confirms that parasite activated the dose-dependent autophagy to circumvent the anti-plasmodial defenses. The gene transcription profiling of P. berghei (pathogen) and mice (host) further suggested that the activation of autophagy-like escape mechanism evading the anti-plasmodial defenses could be a double-edged sword 6 ( Figures 10 B and 10C). Autophagy helped parasite escape the anti-plasmodial defenses and withstand drug pressure to confer the extended survival by inhibiting the programmed cell death ( Figures 4 and 10 C).…”

“…Oleuropein (OLP) possessing anti-inflammatory, anti-oxidants, immunomodulatory activity is known to activate autophagy. 5 , 6 , 7 , 8 Hence. human THP-1 macrophage model of inflammation (MMI; antigen [LPS]-stimulated macrophages) was developed to confirm the inflammatory and signaling properties of OLP.…”

Homeostasis Maintenance in Plasmodium-Infected Placentas: Is There a Role for Placental Autophagy During Malaria in Pregnancy?

“…However, experiments with null-VAR2CSA parasites were missing so we cannot rule out the hypothesis that observed effects might still occur in a binding independent manner and simply due to parasite antigen recognition. Plasmodium -derived microvesicles, which carry parasite-derived antigens and activate the immune system, are transferred to astrocytes by LC3-associated phagocytosis, with implications to neuroinflammation and cerebral malaria pathogenesis ( 91 ). Besides, microvesicles can also trigger inflammation by activating TLR4-MyD88 axis ( 92 ), which is linked to autophagy modulation as previously discussed.…”