Importance of Type I and III Interferons at Respiratory and Intestinal Barrier Surfaces

Abstract

Interferons (IFNs) constitute the first line of defense against microbial infections particularly against viruses. They provide antiviral properties to cells by inducing the expression of hundreds of genes known as interferon-stimulated genes (ISGs). The two most important IFNs that can be produced by virtually all cells in the body during intrinsic innate immune response belong to two distinct families: the type I and type III IFNs. The type I IFN receptor is ubiquitously expressed whereas the type III IFN receptor’s expression is limited to epithelial cells and a subset of immune cells. While originally considered to be redundant, type III IFNs have now been shown to play a unique role in protecting mucosal surfaces against pathogen challenges. The mucosal specific functions of type III IFN do not solely rely on the restricted epithelial expression of its receptor but also on the distinct means by which type III IFN mediates its anti-pathogen functions compared to the type I IFN. In this review we first provide a general overview on IFNs and present the similarities and differences in the signal transduction pathways leading to the expression of either type I or type III IFNs. By highlighting the current state-of-knowledge of the two archetypical mucosal surfaces (e.g. the respiratory and intestinal epitheliums), we present the differences in the signaling cascades used by type I and type III IFNs to uniquely induce the expression of ISGs. We then discuss in detail the role of each IFN in controlling pathogen infections in intestinal and respiratory epithelial cells. Finally, we provide our perspective on novel concepts in the field of IFN (stochasticity, response heterogeneity, cellular polarization/differentiation and tissue microenvironment) that we believe have implications in driving the differences between type I and III IFNs and could explain the preferences for type III IFNs at mucosal surfaces.

Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses

“…For example, the host response to viral infection is dependent on the expression kinetics of type I and III IFNs, among others. The expression of IFNβ and IFNλ mRNA peaked at 16 and 24 hpi, respectively, in intestinal enteroids infected with reovirus [41], consistent with the notion that type III IFN responses are generally of lower magnitude, slower kinetics and longer duration compared to type I IFN responses [46]. Thus, sampling of the IFN Informed Consent Statement: Not applicable.…”

Interferon-Lambda 1 Inhibits Staphylococcus aureus Colonization in Human Primary Keratinocytes

“…The relationship between IFN-λs and epithelial barrier protection in various organs, e.g. respiratory tract, lungs, and gastrointestinal tract had been well-established ( Lozhkov et al, 2020 ; Stanifer et al, 2020 ). The ex vivo infection model showed that the barrier gene FLG and IVL were generally inhibited in S. aureus infection model.…”

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease

“…They need to act tolerogenic to the vast amount of bacterial commensals but at the same time also be responsive to detrimental pathogens. In this context, there is increasing evidence that both type I and type III IFNs are important for the maintenance of the intestinal epithelial barrier integrity and the control of adaptive immune responses including antiviral responses ( 81 , 82 ). In the intestine, type I IFNs are for example continuously produced by CD11c + DCs of the lamina propria ( 83 ).…”