Interferons (IFNs) are fundamental mediators and regulators of the host immune response to viruses and other microbial agents. Type I and type III IFNs (also known as IFN-λ) are some of the first cytokines to be induced upon detection of viral infections. Signaling through their specific receptors leads to the activation of a similar signaling cascade that triggers the expression of a common set of IFN-stimulated genes (ISGs) with antiviral effector functions. The main feature that makes each of these families of IFNs unique and nonredundant is the existence of distinct receptors that differentiate them in their ability to act on virtually every cell type (type I IFNs) or exclusively on epithelial cells and a subset of immune cells (type III IFNs). Despite inducing a widely overlapping set of genes, IFN-I can mount a stronger proinflammatory response compared to IFN-III. This, coupled with the earlier induction of IFN-III upon infection, has led to the classification of IFN-III as front-line defenders of mucosal surfaces with the ability to initiate an early antiviral response with minimal tissue-damaging effects. If their response is insufficient the system shifts to the more potent and broader-acting antiviral and inflammatory IFN-I response that can cause immunopathology. In the course of my thesis, I have tested the hypothesis that also IFN-III contribute to immunopathology at barrier sites such as the respiratory and gastrointestinal epithelia during viral infections and inflammatory bowel disease/radiation-induced injury respectively. First, my colleagues and I found that in a mouse model where we mimicked the induction of antiviral responses in the respiratory tract, IFN-III produced by lung dendritic cells inhibited the proliferation of lung epithelial cells leading to an impairment in barrier restoration and an increase in susceptibility to bacterial infections. Then we measured IFN responses along the respiratory tract of COVID-19 patients. We uncovered that in the upper airways expression of IFN-I/III correlated with viral load and elderly patients, that have a higher risk of developing severe COVID-19, had a dysregulation in the IFN response. A strong expression of IFN-λ1, IFN-λ3 and ISGs characterized the upper airways of mild patients. IFN-I and IFN-λ2 together with antiproliferative and proapoptotic genes were upregulated along all the respiratory tract of severe COVID-19 patients, suggesting that they might contribute to the impairment of epithelium restitution. Finally, we demonstrated that IFN-III delayed colon and small intestine repair after dextran sulfate sodium-induced colitis and radiation-induced injury by triggering cell death of epithelial cells via the formation of a novel protein complex that includes Z-DNA binding protein (ZBP1) and gasdermin C (GSDMC). Our findings challenge the role of IFN-III as protectors of mucosal barriers as they indicate that a dysregulated IFN-III response holds the potential to contribute to immunopathology. Therefore, the clinical use of type III IFNs should be designed in such a way that their tissue-damaging functions are avoided and their beneficial effects are maximized.

Gli interferoni (IFN) sono mediatori e regolatori fondamentali della risposta immunitaria dell'ospite a virus e ad altri agenti microbici. Gli IFN di tipo I e di tipo III (o IFN-λ) sono tra le prime citochine ad essere indotte in seguito a infezioni virali. Il legame tra gli IFN e i rispettivi recettori attiva vie di trasduzione del segnale simili tra loro che inducono l'espressione di geni stimolati dagli IFN (ISG) con funzioni antivirali. La caratteristica principale che rende ciascuna di queste famiglie di IFN unica e non ridondante è l'esistenza di recettori distinti che fanno sì che gli IFN-I attivino una risposta ubiquitaria e che gli IFN-III agiscano esclusivamente sulle cellule epiteliali e su un sottoinsieme di cellule immunitarie. Ulteriori distinzioni riguardano la natura meno infiammatoria degli IFN-III e la loro induzione solitamente anticipata rispetto a quella degli IFN-I. Pertanto gli IFN-III sono considerati i difensori di prima linea delle mucose con la capacità di attivare una risposta antivirale precoce senza causare danno tissutale. Se la loro azione risulta insufficiente a contenere l’infezione, il sistema passa all’induzione degli IFN-I, i quali generano una risposta antivirale e infiammatoria più potente e a livello sistemico, che tuttavia può portare ad immunopatologia. Nel corso della mia tesi ho verificato l'ipotesi secondo cui anche gli IFN-III possano causare immunopatologia, in particolare durante infezioni virali delle vie respiratorie e in contesti di danno all’epitelio gastrointestinale in malattie infiammatorie croniche intestinali e lesioni da radiazioni. In primo luogo, io e i miei colleghi abbiamo dimostrato che in un polmone in cui è stata indotta una risposta antivirale, gli IFN-III prodotti dalle cellule dendritiche inibiscono la proliferazione delle cellule epiteliali portando ad una compromissione del rigenerazione della barriera e ad un aumento della suscettibilità ad infezioni batteriche. In seguito abbiamo analizzato la produzione di IFN lungo il tratto respiratorio di pazienti affetti da COVID-19. Abbiamo trovato che, nelle alte vie aeree, l'espressione di IFN-I/III correla con la carica virale e che negli anziani, che presentano un maggiore rischio di sviluppare una patologia severa, questa correlazione è più debole o assente. Una forte espressione di IFN-λ1, IFN-λ3 e ISG caratterizza le alte vie aeree di pazienti con sintomatologia lieve, mentre risultano fortemente espressi gli IFN-I, IFN-λ2 e un insieme di geni antiproliferativi e proapoptotici lungo tutto il tratto respiratorio di pazienti ospedalizzati, suggerendo che possano ostacolare il processo di riparazione dell’epitelio. Infine, abbiamo dimostrato che gli IFN-III ritardano la rigenerazione dell'intestino tenue e del colon in seguito a danno da radiazioni o da colite indotta da destrano sodio solfato, poiché contribuiscono a indurre la morte cellulare delle cellule epiteliali tramite la formazione di un complesso proteico costituito da Z-DNA binding protein (ZBP1) e gasdermin C (GSDMC). I nostri risultati mettono in discussione il ruolo degli IFN-III come protettori delle mucose poiché indicano che quando non propriamente regolati possono causare immunopatologia. Queste evidenze portano alla necessità di progettare l’uso clinico degli IFN di tipo III in modo da evitare le loro funzioni dannose per i tessuti e massimizzarne gli effetti benefici.

(2023). Type III Interferons: Running Interference with Mucosal Repair.. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2023).

Type III Interferons: Running Interference with Mucosal Repair.

SPOSITO, BENEDETTA
2023

Abstract

Interferons (IFNs) are fundamental mediators and regulators of the host immune response to viruses and other microbial agents. Type I and type III IFNs (also known as IFN-λ) are some of the first cytokines to be induced upon detection of viral infections. Signaling through their specific receptors leads to the activation of a similar signaling cascade that triggers the expression of a common set of IFN-stimulated genes (ISGs) with antiviral effector functions. The main feature that makes each of these families of IFNs unique and nonredundant is the existence of distinct receptors that differentiate them in their ability to act on virtually every cell type (type I IFNs) or exclusively on epithelial cells and a subset of immune cells (type III IFNs). Despite inducing a widely overlapping set of genes, IFN-I can mount a stronger proinflammatory response compared to IFN-III. This, coupled with the earlier induction of IFN-III upon infection, has led to the classification of IFN-III as front-line defenders of mucosal surfaces with the ability to initiate an early antiviral response with minimal tissue-damaging effects. If their response is insufficient the system shifts to the more potent and broader-acting antiviral and inflammatory IFN-I response that can cause immunopathology. In the course of my thesis, I have tested the hypothesis that also IFN-III contribute to immunopathology at barrier sites such as the respiratory and gastrointestinal epithelia during viral infections and inflammatory bowel disease/radiation-induced injury respectively. First, my colleagues and I found that in a mouse model where we mimicked the induction of antiviral responses in the respiratory tract, IFN-III produced by lung dendritic cells inhibited the proliferation of lung epithelial cells leading to an impairment in barrier restoration and an increase in susceptibility to bacterial infections. Then we measured IFN responses along the respiratory tract of COVID-19 patients. We uncovered that in the upper airways expression of IFN-I/III correlated with viral load and elderly patients, that have a higher risk of developing severe COVID-19, had a dysregulation in the IFN response. A strong expression of IFN-λ1, IFN-λ3 and ISGs characterized the upper airways of mild patients. IFN-I and IFN-λ2 together with antiproliferative and proapoptotic genes were upregulated along all the respiratory tract of severe COVID-19 patients, suggesting that they might contribute to the impairment of epithelium restitution. Finally, we demonstrated that IFN-III delayed colon and small intestine repair after dextran sulfate sodium-induced colitis and radiation-induced injury by triggering cell death of epithelial cells via the formation of a novel protein complex that includes Z-DNA binding protein (ZBP1) and gasdermin C (GSDMC). Our findings challenge the role of IFN-III as protectors of mucosal barriers as they indicate that a dysregulated IFN-III response holds the potential to contribute to immunopathology. Therefore, the clinical use of type III IFNs should be designed in such a way that their tissue-damaging functions are avoided and their beneficial effects are maximized.
ZANONI, IVAN
Interferoni; COVID-19; Morbo di Crohn; Infezioni virali; Immunità innata
Interferons; COVID-19; Crohn’s Disease; Viral infections; Innate Immunity
MED/04 - PATOLOGIA GENERALE
English
23-gen-2023
MEDICINA TRASLAZIONALE E MOLECOLARE - DIMET
35
2021/2022
open
(2023). Type III Interferons: Running Interference with Mucosal Repair.. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2023).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/402377
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