eprintid: 25615
rev_number: 19
eprint_status: archive
userid: 4098
dir: disk0/00/02/56/15
datestamp: 2018-11-15 09:29:00
lastmod: 2019-01-11 09:44:44
status_changed: 2018-11-15 09:29:00
type: doctoralThesis
metadata_visibility: show
creators_name: Pervolaraki, Kalliopi
title: Functional differences in type I versus type III interferon mediated immunity
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
cterms_swd: intestinal epithelial cells
cterms_swd: interferon
cterms_swd: interferon stimulated genes
cterms_swd: antiviral immunity
cterms_swd: mucosal immunity
cterms_swd: data-driven mathematical modelling
abstract: Intestinal epithelial cells (IECs) lining the surface of our gastrointestinal tract tolerate the presence of the commensal microbiota, while maintaining responsiveness against enteric pathogens. How IECs regulate their innate immune response to maintain this finely tuned balance and establish an immune-homeostatic state in the gut remains unclear. Interferons (IFNs) are cytokines produced upon viral infection. While type I IFN receptors are ubiquitously expressed, type III IFN receptors are preferentially expressed on epithelial cells. This epithelium specificity strongly suggests exclusive functions at epithelial surfaces, but the relative roles of type I and type III IFNs in the establishment of an antiviral response in human IECs are not clearly defined.
Here, we utilized human mini-gut organoid cultures and human colon cell lines to delve into the antiviral properties of type I versus type III IFNs in the gut. We could show that although primary human IECs, produce transcript levels for both IFNs, they secrete only type III IFNs in the supernatant upon viral challenge. However, using genetic ablation of either type I or type III IFN receptors, we revealed that human IECs respond to both IFNs, by independently establishing an antiviral state, responsible for combating enteric viral infection. Importantly, we could identify differences in the establishment of each IFN antiviral activity. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen- activated protein kinases signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. In addition, we showed that while type I IFN signaling is characterized by an acute strong induction of ISGs and confers fast antiviral protection, type III IFN mediated antiviral protection is characterized by a slow weak induction of ISGs. Combining data-driven mathematical modeling with experimental validation, we demonstrated that these kinetic differences are intrinsic to each signaling pathway and not due to different expression levels of the corresponding IFN receptors.
In conclusion, our results strongly suggest that type III IFN is specifically tailored to act on epithelial cells not only due to the restriction of its receptor but also by providing IECs with a distinct antiviral environment compared to type I IFN, which allows for efficient protection against pathogens without producing excessive inflammatory signals. We propose that this specific antiviral environment is key for mucosal surfaces, which are often challenged with the extracellular environment, to maintain gut homeostasis.
date: 2018
id_scheme: DOI
id_number: 10.11588/heidok.00025615
ppn_swb: 1653326549
own_urn: urn:nbn:de:bsz:16-heidok-256153
date_accepted: 2018-09-18
advisor: HASH(0x559e37bb8c18)
language: eng
bibsort: PERVOLARAKFUNCTIONAL2018
full_text_status: public
place_of_pub: Heidelberg
citation:   Pervolaraki, Kalliopi  (2018) Functional differences in type I versus type III interferon mediated immunity.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/25615/1/thesis%20260618_last%20new.pdf