Abstract
Plasmodium parasites undergo a dramatic transformation during the liver stage of their life cycle, amplifying over 10,000-fold inside infected hepatocytes within a few days. Such a rapid growth requires large-scale interactions with, and manipulations of, host cell functions. Whereas hepatocyte polarity is well-known to be critical for liver function, little is presently known about its involvement during the liver stage of Plasmodium development. Apical domains of hepatocytes are critical components of their polarity machinery and constitute the bile canalicular network, which is central to liver function. Here, we employed high resolution 3-D imaging and advanced image analysis of Plasmodium-infected liver tissues to show that the parasite associates preferentially with the apical domain of hepatocytes and induces alterations in the organization of these regions, resulting in localized changes in the bile canalicular architecture in the liver tissue. Pharmacological perturbation of the bile canalicular network by modulation of AMPK activity reduces the parasite's association with bile canaliculi and arrests the parasite development. Our findings using Plasmodium-infected liver tissues reveal a host-Plasmodium interaction at the level of liver tissue organization. We demonstrate for the first time a role for bile canaliculi, a central component of the hepatocyte polarity machinery, during the liver stage of Plasmodium development.
Highlights
Plasmodium parasites undergo a dramatic amplification during the liver stage of their life cycle, when an individual sporozoite infecting a hepatocyte multiplies inside a parasitophorous vacuole (PV) to produce several thousand infective merozoites (Prudencio et al, 2006; Vaughan and Kappe, 2017)
Our results show that parasite growth in vivo is not linear, displaying only a modest increase in PV volume between 24 and 33 hpi, followed by a steep increase between 33 and 48 hpi (Figure 1C), showing that the period between 33 and 48 hpi marks a phase of rapid parasite development in vivo
Salicylate treatment significantly decreases the contact of the apical domain with the PV membrane (PVM) at 33 hpi, as shown by the reduced surface voxels of CD13 on the PVM (Figure 4E), indicating that the contact between the apical domain and the PVM is decreased during AMPK activation. In view of these results, we propose that the salicylate-mediated reduction in the contact of the PVM with the hepatocyte apical domain contributes to the arrest of parasite growth in vivo
Summary
Plasmodium parasites undergo a dramatic amplification during the liver stage of their life cycle, when an individual sporozoite infecting a hepatocyte multiplies inside a parasitophorous vacuole (PV) to produce several thousand infective merozoites (Prudencio et al, 2006; Vaughan and Kappe, 2017). Unlike a columnar epithelial cell, where the entire surface facing a luminal cavity is apical, hepatocytes have apical domains spanning the cell as “bands” that connect in 3 dimensions to form the highly ramified bile canalicular (BC) network. This network constitutes the first level of branching in the complex bile duct tree, which eventually drains into the gall bladder (Elias, 1949; Treyer and Musch, 2013; Gissen and Arias, 2015). Whether these processes are involved in the liver stage of Plasmodium infection is not presently known
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