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2021-11-23Zeitschriftenartikel
Dissection of Barrier Dysfunction in Organoid-Derived Human Intestinal Epithelia Induced by Giardia duodenalis
dc.contributor.authorHolthaus, David
dc.contributor.authorKraft, Martin R.
dc.contributor.authorKrug, Susanne M.
dc.contributor.authorWolf, Silver
dc.contributor.authorMüller, Antonia
dc.contributor.authorDelgado-Betancourt, Estefanía
dc.contributor.authorSchorr, Madeleine
dc.contributor.authorHolland, Gudrun
dc.contributor.authorKnauf, Felix
dc.contributor.authorSchulzke, Joerg-Dieter
dc.contributor.authorAebischer, Toni
dc.contributor.authorKlotz, Christian
dc.date.accessioned2024-06-13T11:42:01Z
dc.date.available2024-06-13T11:42:01Z
dc.date.issued2021-11-23none
dc.identifier.other10.1053/j.gastro.2021.11.022
dc.identifier.urihttp://edoc.rki.de/176904/11723
dc.description.abstractBACKGROUND & AIMS: The protozoa Giardia duodenalis is a major cause of gastrointestinal illness worldwide, but un- derlying pathophysiological mechanisms remain obscure, partly due to the absence of adequate cellular models. We aimed at overcoming these limitations and recapitulating the authentic series of pathogenic events in the primary human duodenal tissue by using the human organoid sys- tem. METHODS: We established a compartmentalized cellular transwell system with electrophysiological and barrier properties akin to duodenal mucosa and dissected the events leading to G. duodenalis-induced barrier break- down by functional analysis of transcriptional, electro- physiological, and tight junction components. RESULTS: Organoid-derived cell layers of different donors showed a time- and parasite load-dependent leak flux indicated by collapse of the epithelial barrier upon G. duodenalis infection. Gene set enrichment analysis suggested major expression changes, including gene sets contributing to ion transport and tight junction structure. Solute carrier family 12 member 2 and cystic fibrosis transmembrane conductance regulator- dependent chloride secretion was reduced early after infec- tion, while changes in the tight junction composition, locali- zation, and structural organization occurred later as revealed by immunofluorescence analysis and freeze fracture electron microscopy. Functionally, barrier loss was linked to the adenosine 30,50-cyclic monophosphate (cAMP)/protein kinase A-cAMP response element-binding protein signaling pathway. CONCLUSIONS: Data suggest a previously unknown sequence of events culminating in intestinal barrier dysfunction upon G. duodenalis infection during which al- terations of cellular ion transport were followed by breakdown of the tight junctional complex and loss of epithelial integrity, events involving a cAMP/protein kinase A-cAMP response element-binding protein mechanism. These findings and the newly established organoid-derived model to study G. duodenalis infection may help to explore new options for intervening with disease and infection, in particular relevant for chronic cases of giardiasis.eng
dc.language.isoengnone
dc.publisherRobert Koch-Institut
dc.rights(CC BY 3.0 DE) Namensnennung 3.0 Deutschlandger
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/de/
dc.subjectgiardiasiseng
dc.subjecthost-parasite interactioneng
dc.subjectpathogenesiseng
dc.subjectintestinal protozoaeng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titleDissection of Barrier Dysfunction in Organoid-Derived Human Intestinal Epithelia Induced by Giardia duodenalisnone
dc.typearticle
dc.identifier.urnurn:nbn:de:0257-176904/11723-4
dc.type.versionpublishedVersionnone
local.edoc.container-titleGastroenterologynone
local.edoc.container-issn1528-0012none
local.edoc.pages15none
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.sciencedirect.com/journal/gastroenterologynone
local.edoc.container-publisher-nameElseviernone
local.edoc.container-volume162none
local.edoc.container-issue3none
local.edoc.container-reportyear2021none
local.edoc.container-firstpage844none
local.edoc.container-lastpage858none
dc.description.versionPeer Reviewednone

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