title: LAP-like process as an immune mechanism downstream of IFN-γ in control of the human malaria Plasmodium vivax liver stage.
abstract: IFN-γ is a major regulator of immune functions and has been shown to induce liver-stage Plasmodium elimination both in vitro and in vivo. The molecular mechanism responsible for the restriction of liver-stage Plasmodium downstream of IFN-γ remains uncertain, however. Autophagy, a newly described immune defense mechanism, was recently identified as a downstream pathway activated in response to IFN-γ in the control of intracellular infections. We thus hypothesized that the killing of liver-stage malarial parasites by IFN-γ involves autophagy induction. Our results show that whereas IFN-γ treatment of human hepatocytes activates autophagy, the IFN-γ-mediated restriction of liver-stage Plasmodium vivax depends only on the downstream autophagy-related proteins Beclin 1, PI3K, and ATG5, but not on the upstream autophagy-initiating protein ULK1. In addition, IFN-γ enhanced the recruitment of LC3 onto the parasitophorous vacuole membrane (PVM) and increased the colocalization of lysosomal vesicles with P. vivax compartments. Taken together, these data indicate that IFN-γ mediates the control of liver-stage P. vivax by inducing a noncanonical autophagy pathway resembling that of LC3-associated phagocytosis, in which direct decoration of the PVM with LC3 promotes the fusion of P. vivax compartments with lysosomes and subsequent killing of the pathogen. Understanding the hepatocyte response to IFN-γ during Plasmodium infection and the roles of autophagy-related proteins may provide an urgently needed alternative strategy for the elimination of this human malaria.
authors.affiliation: Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Rachasak
authors.initials: R
authors.lastname: Boonhok
authors.affiliation: Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Nattawan
authors.initials: N
authors.lastname: Rachaphaew
authors.affiliation: Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Apisak
authors.initials: A
authors.lastname: Duangmanee
authors.affiliation: Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Chobson
authors.affiliation: Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sittiporn
authors.initials: S
authors.lastname: Pattaradilokrat
authors.affiliation: Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;
authors.forename: Pongsak
authors.initials: P
authors.lastname: Utaisincharoen
authors.affiliation: Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; jetsumon.pra@mahidol.ac.th marisa.pon@mahidol.ac.th.
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.affiliation: Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; jetsumon.pra@mahidol.ac.th marisa.pon@mahidol.ac.th.
authors.forename: Marisa
authors.identifier: 0000-0002-2889-1314
authors.initials: M
authors.lastname: Ponpuak
mesh_terms: D006801:Humans; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000276:immunology; D016780:Malaria, Vivax; D019869:Phosphatidylinositol 3-Kinases; D010966:Plasmodium vivax
chemical_list: D019869:Phosphatidylinositol 3-Kinases
keywords: IFN-γ; LC3-associated phagocytosis; autophagy; malaria