期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 25, 页码 E3519-E3528出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1525606113
关键词
autophagy; LC3-associated phagocytosis; IFN-gamma; malaria
资金
- Development and Promotion of Science and Technology Talents Project [023/2557]
- Faculty of Science, Mahidol University
- Bill & Melinda Gates Foundation
IFN-gamma 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-gamma remains uncertain, however. Autophagy, a newly described immune defense mechanism, was recently identified as a downstream pathway activated in response to IFN-gamma in the control of intracellular infections. We thus hypothesized that the killing of liver-stage malarial parasites by IFN-gamma involves autophagy induction. Our results show that whereas IFN-gamma treatment of human hepatocytes activates autophagy, the IFN-gamma-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-gamma 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-gamma 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-gamma during Plasmodium infection and the roles of autophagy-related proteins may provide an urgently needed alternative strategy for the elimination of this human malaria.
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