Bacterial detection by NAIP/NLRC4 elicits prompt contractions of intestinal epithelial cell layers

Open access
Date
2021-04-20Type
- Journal Article
Citations
Cited 13 times in
Web of Science
Cited 13 times in
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Abstract
The gut epithelium serves to maximize the surface for nutrient and fluid uptake, but at the same time must provide a tight barrier to pathogens and remove damaged intestinal epithelial cells (IECs) without jeopardizing barrier integrity. How the epithelium coordinates these tasks remains a question of significant interest. We used imaging and an optical flow analysis pipeline to study the dynamicity of untransformed murine and human intestinal epithelia, cultured atop flexible hydrogel supports. Infection with the pathogen Salmonella Typhimurium (S.Tm) within minutes elicited focal contractions with inward movements of up to ∼1,000 IECs. Genetics approaches and chimeric epithelial monolayers revealed contractions to be triggered by the NAIP/NLRC4 inflammasome, which sensed type-III secretion system and flagellar ligands upon bacterial invasion, converting the local tissue into a contraction epicenter. Execution of the response required swift sublytic Gasdermin D pore formation, ion fluxes, and the propagation of a myosin contraction pulse across the tissue. Importantly, focal contractions preceded, and could be uncoupled from, the death and expulsion of infected IECs. In both two-dimensional monolayers and three-dimensional enteroids, multiple infection-elicited contractions coalesced to produce shrinkage of the epithelium as a whole. Monolayers deficient for Caspase-1(-11) or Gasdermin D failed to elicit focal contractions but were still capable of infected IEC death and expulsion. Strikingly, these monolayers lost their integrity to a markedly higher extent than wild-type counterparts. We propose that prompt NAIP/NLRC4/Caspase-1/Gasdermin D/myosin–dependent contractions allow the epithelium to densify its cell packing in infected regions, thereby preventing tissue disintegration due to the subsequent IEC death and expulsion process. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000480358Publication status
publishedExternal links
Journal / series
Proceedings of the National Academy of Sciences of the United States of AmericaVolume
Pages / Article No.
Publisher
National Academy of SciencesSubject
bacterial infection; epithelium; organoid; inflammasome; contractionOrganisational unit
03589 - Hardt, Wolf-Dietrich / Hardt, Wolf-Dietrich
Funding
192567 - Mechanisms controlling the Salmonella Typhimurium gut infection (SNF)
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Show all metadata
Citations
Cited 13 times in
Web of Science
Cited 13 times in
Scopus
ETH Bibliography
yes
Altmetrics