Long-term live imaging reveals cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms

Prado, Monica; Eickel, Nina; De Niz Hidalgo, Mariana Isabel; Heitmann, Anna; Agop Nersesian, Carolina; Wacker, Rahel Corina; Schmuckli-Maurer, Jacqueline; Caldelari, Reto; Janse, Chris J; Khan, Shahid M; May, Jürgen; Meyer, Christian G; Heussler, Volker (2015). Long-term live imaging reveals cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms. Autophagy, 11(9), pp. 1561-1579. Landes Bioscience 10.1080/15548627.2015.1067361

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Plasmodium parasites are transmitted by Anopheles mosquitoes to the mammalian host and actively infect hepatocytes after passive transport in the bloodstream to the liver. In their target host hepatocyte, parasites reside within a parasitophorous vacuole (PV). In the present study it was shown that the parasitophorous vacuole membrane (PVM) can be targeted by autophagy marker proteins LC3, ubiquitin, and SQSTM1/p62 as well as by lysosomes in a process resembling selective autophagy. The dynamics of autophagy marker proteins in individual Plasmodium berghei-infected hepatocytes were followed by live imaging throughout the entire development of the parasite in the liver. Although the host cell very efficiently recognized the invading parasite in its vacuole, the majority of parasites survived this initial attack. Successful parasite development correlated with the gradual loss of all analyzed autophagy marker proteins and associated lysosomes from the PVM. However, other autophagic events like nonselective canonical autophagy in the host cell continued. This was indicated as LC3, although not labeling the PVM anymore, still localized to autophagosomes in the infected host cell. It appears that growing parasites even benefit from this form of nonselective host cell autophagy as an additional source of nutrients, as in host cells deficient for autophagy, parasite growth was retarded and could partly be rescued by the supply of additional amino acid in the medium. Importantly, mouse infections with P. berghei sporozoites confirmed LC3 dynamics, the positive effect of autophagy activation on parasite growth, and negative effects upon autophagy inhibition.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology > Malaria
08 Faculty of Science > Department of Biology > Institute of Cell Biology
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

De Niz Hidalgo, Mariana Isabel; Agop Nersesian, Carolina; Wacker, Rahel Corina; Caldelari, Reto and Heussler, Volker

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 630 Agriculture
500 Science

ISSN:

1554-8627

Publisher:

Landes Bioscience

Language:

English

Submitter:

Volker Heussler

Date Deposited:

20 Aug 2015 10:33

Last Modified:

16 Jan 2019 15:20

Publisher DOI:

10.1080/15548627.2015.1067361

PubMed ID:

26208778

Uncontrolled Keywords:

ATG, autophagy related Atg8, (yeast) autophagy-related 8 CLS, confocal line scanning CSP, circumsporozoite protein CTSD, cathepsin D Cytosolic immune response, LC3 DAPI, 4′,6-diamidino-2-phenylindole DMEM, Dulbecco modified Eagle medium EBSS, Earle balanced salt solution ECACC, European Collection of Cell Cultures EM, electron microscopy Exp1, exported protein 1 FACS, fluorescent-activated cell sorting FCS, fetal calf serum GFP, green fluorescent protein H&E, hematoxylin and eosin HepG2, human hepatoma cells IFA, immunofluorescence assay LAMP1, lysosomal-associated membrane protein 1 LAP, LC3-associated phagocytosis LGALS, galectins MAP1LC3/LC3, microtubule-associated protein 1 light chain 3 MEFs, mouse embryonic fibroblasts MEM, minimum essential medium MTOR, mechanistic target of rapamycin (serine/threonine kinase) PBS, phosphate-buffered saline PE, phosphatidylethanolamine PM, parasite membrane PV, parasitophorous vacuole PVM, parasitophorous vacuole membrane Pb, Plasmodium berghei PbmCherry, Plasmodium berghei expressing mCherry fluorescent protein Plasmodium liver-stage PtdIns3P, phosphatidylinositol-3-phosphate RFP, red fluorescence protein SD, standard deviation SQSTM1, sequestosome 1 STED, stimulated emission depletion UIS4, upregulated in infectious sporozoites gene 4 WT, wild type atg5−/−, autophagy-related 5 knockout e-schz, early schizont hpi, hours postinfection l-schz, late schizont long term live imaging malaria selective autophagy spz, sporozoite ubiquitin

BORIS DOI:

10.7892/boris.71017

URI:

https://boris.unibe.ch/id/eprint/71017

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