The gastrointestinal tract is composed of a single layer of epithelial cells that separates the inside of the body from a complex and vast community of harmless micro-organisms (the microbiome) that live in the intestine and provide essential functions to the host. Underneath the epithelial lining is the largest population of immune cells in the mammalian body that serves as a critical monitor of these micro-organisms sensing the presence of potential disease-causing pathogens. Inflammatory bowel disease (IBD) is thought to result when the immune system inappropriately responds to the microbiome with an aggressive attack resulting in intestinal inflammation and damage. The immune signals that recognize and respond to bacterial and viral components of the microbiome are incompletely understood. Interferons (IFN) play a critical role in this process with diverse activities but are most known for their inherent anti-viral activities. IFNs are divided into three classes: type I IFNs (that comprise IFN?, ? and others), type II IFNs (IFN?) and the more recently identified type III IFNs or IFN?s. Most studies investigating the relationship of IFNs and IBD have focused on the relevance of type I IFNs. The cellular targets of IFN?s are much more limited and defined, compared to those of type I IFNs, because the specific receptor for IFN?, IFNLR1, is almost exclusively expressed in epithelial cells. We have recently demonstrated that IFNLR1 is also expressed on neutrophils. More importantly, we have demonstrated in mice that: 1) IFN? targets neutrophils; 2) IFN? blockade enhances inflammation; 3) commensal enteric viruses regulate IFN?-dependent responses; and 4) exogenous IFN? administration suppresses intestinal inflammation. Further support of a critical role for IFN? in mucosal homeostasis beyond murine biology comes from our recent identification of an infant with very early onset IBD (VEOIBD) that has homozygous damaging mutations in two IFN?s. Collectively, these findings serve the basis of our hypothesis that IFN? is a critical modulator of mucosal homoeostasis in mice and humans and may be an attractive therapeutic agent for IBD. In this project, we will benefit from the joint expertise of two co-principal investigators (Snapper and Zanoni) and capitalize on a vast compilation of conditionally targeted murine models, deep expertise in murine models of IBD, and relevant patient-derived materials. We propose four aims where we plan: 1) to assess the protective and therapeutic role of IFN? in acute and chronic models of colitis; 2) to determine the cell population(s) that mediates IFN?- dependent colitis protection and therapeutic responses; 3) to assess the role of microbiota in IFN?-dependent regulation of intestinal inflammation and IFN?-dependent therapeutic responses; 4) to assess how mutations in human IFN? alter mucosal homeostasis. Completion of the aims of this grant will aid in defining the precise mechanisms by which IFN?s protect against IBD in mice and humans and will explore whether IFN?s can be used as a therapeutic agent for the treatment of IBD.

Public Health Relevance

Inflammatory bowel disease (IBD) is thought to result when the intestinal immune system inappropriately responds to the complex and vast community of harmless micro-organisms (the microbiome) with an aggressive attack resulting in intestinal inflammation and damage. The immune signals that recognize and respond to bacterial and viral components of the microbiome are incompletely understood. This application focuses on a relatively unexplored group of immune molecules known as Type III interferons (i.e., IFN?s) that respond to the microbiome and that we have identified as important in protecting mice and humans from IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK115217-04
Application #
9989843
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2017-08-01
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Ning-Ning; Uppuluri, Priya; Broggi, Achille et al. (2018) Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog 14:e1007076
Radaelli, F; D'Alfonso, L; Collini, M et al. (2017) ?MAPPS: a novel phasor approach to second harmonic analysis for in vitro-in vivo investigation of collagen microstructure. Sci Rep 7:17468
Zanoni, Ivan; Granucci, Francesca; Broggi, Achille (2017) Interferon (IFN)-? Takes the Helm: Immunomodulatory Roles of Type III IFNs. Front Immunol 8:1661
Santus, William; Barresi, Simona; Mingozzi, Francesca et al. (2017) Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems. Sci Immunol 2:
Zanoni, Ivan; Tan, Yunhao; Di Gioia, Marco et al. (2017) By Capturing Inflammatory Lipids Released from Dying Cells, the Receptor CD14 Induces Inflammasome-Dependent Phagocyte Hyperactivation. Immunity 47:697-709.e3
Prosperi, Davide; Colombo, Miriam; Zanoni, Ivan et al. (2017) Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases. Semin Immunol 34:61-67
Broggi, Achille; Tan, Yunhao; Granucci, Francesca et al. (2017) IFN-? suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat Immunol 18:1084-1093