title: In Vivo Function of PTEX88 in Malaria Parasite Sequestration and Virulence.
abstract: Malaria pathology is linked to remodeling of red blood cells by eukaryotic Plasmodium parasites. Central to host cell refurbishment is the trafficking of parasite-encoded virulence factors through the Plasmodium translocon of exported proteins (PTEX). Much of our understanding of its function is based on experimental work with cultured Plasmodium falciparum, yet direct consequences of PTEX impairment during an infection remain poorly defined. Using the murine malaria model parasite Plasmodium berghei, it is shown here that efficient sequestration to the pulmonary, adipose, and brain tissue vasculature is dependent on the PTEX components thioredoxin 2 (TRX2) and PTEX88. While TRX2-deficient parasites remain virulent, PTEX88-deficient parasites no longer sequester in the brain, correlating with abolishment of cerebral complications in infected mice. However, an apparent trade-off for virulence attenuation was spleen enlargement, which correlates with a strongly reduced schizont-to-ring-stage transition. Strikingly, general protein export is unaffected in PTEX88-deficient mutants that mature normally in vitro. Thus, PTEX88 is pivotal for tissue sequestration in vivo, parasite virulence, and preventing exacerbation of spleen pathology, but these functions do not correlate with general protein export to the host erythrocyte. The presented data suggest that the protein export machinery of Plasmodium parasites and their underlying mechanistic features are considerably more complex than previously anticipated and indicate challenges for targeted intervention strategies.
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany Institute of Biology, Humboldt University, Berlin, Germany Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Matz
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Ingmundson
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Costa Nunes
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany Institute of Biology, Humboldt University, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Berlin, Germany Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands Taco.Kooij@radboudumc.nl.
authors.forename: Taco W A
authors.identifier: http://orcid.org/0000-0002-8547-7523
authors.initials: TW
authors.lastname: Kooij
mesh_terms: D000818:Animals; D001921:Brain / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei / Q000254:growth & development / Q000472:pathogenicity*; D021381:Protein Transport; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000469:parasitology; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D013879:Thioredoxins
references.citation: Microbes Infect. 2003 Aug;5(10):897-909
references.pmid: 12919858
references.citation: J Exp Med. 2003 Sep 15;198(6):869-75
references.pmid: 12963693
references.citation: Science. 2004 Dec 10;306(5703):1930-3
references.pmid: 15591202
references.citation: Science. 2004 Dec 10;306(5703):1934-7
references.pmid: 15591203
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11468-73
references.pmid: 16051702
references.citation: Curr Top Microbiol Immunol. 2005;297:103-43
references.pmid: 16265904
references.citation: Mol Biochem Parasitol. 2006 Jan;145(1):60-70
references.pmid: 16242190
references.citation: Neuropathol Appl Neurobiol. 2006 Apr;32(2):177-88
references.pmid: 16599946
references.citation: Annu Rev Pathol. 2007;2:217-49
references.pmid: 18039099
references.citation: PLoS Pathog. 2008 Jun;4(6):e1000086
references.pmid: 18551171
references.citation: Cell. 2008 Jul 11;134(1):48-61
references.pmid: 18614010
references.citation: Nature. 2009 Jun 18;459(7249):945-9
references.pmid: 19536257
references.citation: PLoS Pathog. 2010;6(9):e1001032
references.pmid: 20941396
references.citation: J Exp Med. 2012 Jan 16;209(1):93-107
references.pmid: 22184632
references.citation: J Infect Dis. 2012 Feb 15;205(4):663-71
references.pmid: 22207648
references.citation: Cell Microbiol. 2012 Mar;14(3):343-55
references.pmid: 22188297
references.citation: Mol Microbiol. 2012 Mar;83(6):1229-43
references.pmid: 22329949
references.citation: Int J Med Microbiol. 2012 Oct;302(4-5):179-86
references.pmid: 22898489
references.citation: PLoS Pathog. 2012;8(10):e1002982
references.pmid: 23133375
references.citation: Cell Host Microbe. 2012 Nov 15;12(5):717-29
references.pmid: 23159060
references.citation: Mol Cell Proteomics. 2013 Feb;12(2):426-48
references.pmid: 23197789
references.citation: PLoS Pathog. 2013;9(8):e1003546
references.pmid: 23950716
references.citation: Mol Microbiol. 2013 Sep;89(6):1167-86
references.pmid: 23869529
references.citation: Annu Rev Microbiol. 2013;67:243-69
references.pmid: 23808341
references.citation: Mol Biochem Parasitol. 2013 Sep;191(1):44-52
references.pmid: 24076174
references.citation: Nature. 2014 Jul 31;511(7511):592-5
references.pmid: 25043010
references.citation: Nature. 2014 Jul 31;511(7511):587-91
references.pmid: 25043043
references.citation: Front Cell Infect Microbiol. 2014;4:104
references.pmid: 25191643
references.citation: Pathog Glob Health. 2015 Mar;109(2):46-60
references.pmid: 25789828