Host cell autophagy contributes to Plasmodium liver development

Abstract

Autophagy plays an important role in the defence against intracellular pathogens. However, some microorganisms can manipulate this host cell pathway to their advantage. In this study, we addressed the role of host cell autophagy during Plasmodium berghei liver infection. We show that vesicles containing the autophagic marker LC3 surround parasites from early time-points after invasion and throughout infection and colocalize with the parasitophorous vacuole membrane. Moreover, we show that the LC3-positive vesicles that surround Plasmodium parasites are amphisomes that converge from the endocytic and autophagic pathways, because they contain markers of both pathways. When the host autophagic pathway was inhibited by silencing several of its key regulators such as LC3, Beclin1, Vps34 or Atg5, we observed a reduction in parasite size. We also found that LC3 surrounds parasites in vivo and that parasite load is diminished in a mouse model deficient for autophagy. Together, these results show the importance of the host autophagic pathway for parasite development during the liver stage of Plasmodium infection.

IFN-γ protects hepatocytes againstPlasmodium vivaxinfection via LAP-like degradation of sporozoites

“…In human hepatocytes stimulated with IFN-γ, Boonhok et al (1) demonstrate that a LAP-like process occurs when LC3 is deposited onto the PVM of sporozoites, followed by lysosomal fusion and degradation. This differs from a previously described autophagic pathway, with similarities to selective autophagy, described for P. berghei and P. yoelii sporozoites (5,6). In this pathway, ubiquitin and p62 localize with the PVM in unstimulated hepatocytes, whereas PI3K and Beclin 1 do not.…”

“…On the other hand, autophagy can also be hijacked to deliver nutrients to support the growth of invading pathogens. In malaria, both autophagic clearance and autophagy-mediated growth have recently been shown to play an important role in the development of rodent Plasmodium sporozoites in the liver (5,6). In the basal state, both Plasmodium berghei and Plasmodium yoelii parasites hijack the hepatocyte cell autophagy pathway to gain nutrients to support their rapid growth (5,6).…”

Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

“…However, little is known about intrahepatic Plasmodium stages with regard to interactions between the parasite and the host hepatocyte and their potential for nutrient uptake and/or exchange. Small molecules (up to 800 Da) can cross the PVM freely via specialized transport channels (14), whereas larger molecules might reach the parasite via association and possibly fusion of late endosomes, lysosomes, or amphisomes with the PVM (15)(16)(17)(18)(19).…”

Introductory Chapter: Overview on Autophagy in Burden of Functions

“…Thus, a lack of the "canonical" phagocytic features (such as phagosome biogenesis, the oxidative burst, etc.) in nonprofessional phagocytes is presumably compensated by empowering xenophagy to control and execute all events from pathogen sequestration through degradation [5,6,[18][19][20][21], current book Chpt. 15].…”

“…21]. Thus, many highly virulent intracellular pathogens can subvert and adapt different components of autophagy machinery to establish replicative niches eventually leading to host pathology and death [14,16,18,20]. In conjunction with this, interestingly that upon invagination of hepatocytes, malaria sporozoites are able to adapt autophagy LC3-II protein to form host cell-derived parasitophorous vacuoles; and then to subvert amphisomes-originated from another autophagy pathway-as a nutritional source arranging "own feeding mechanisms", while avoiding degradation by lysosomes [20].…”