Toll-Like Receptor Expression and Induction of Type I and Type III Interferons in Primary Airway Epithelial Cells

Abstract

E pithelial cells lining the airway represent the first barrier to the entry of respiratory viruses and are their main replication target. In addition to its function as a mechanical barrier and in gas exchange, the airway epithelium plays an important role in pathogen detection and is a source of cytokines and other inflammatory mediators that modulate immunity in the respiratory tract (1-7). Airway epithelial cells (AECs) express Toll-like receptor 1 (TLR1) to , and their activation with TLR agonists has been shown to induce the production of several cytokines, chemokines, and antimicrobial peptides. It is worth noting that the majority of these studies have been done at the mRNA level and using continuous cell lines or nonpolarized primary cells as responders to stimulation. Morphology and differentiation are critical in determining infection and immunity of the airway epithelium. First, AECs cultured under air-liquid interface (ALI) differentiate into ciliated cells that are more resistant to virus infection and mount less exacerbated inflammatory responses (12). Second, mucin is a negative regulator of TLR signaling exclusively expressed on the apical surfaces of differentiated AECs (13). Third, multiple receptors and adhesion molecules have a polarized distribution in AECs, i.e., the alpha/beta interferon (IFN-␣/␤) receptor (IFNAR) is exclusively expressed on the basolateral surface (14). Thus, primary polarized AEC cultures provide a valuable system that is a better representation of the airway epithelial microenvironment in vivo than cell lines (15-17).One of the major downstream products of TLR signaling is the IFN family (18). IFNs are a diverse group of cytokines characterized for inducing antiviral resistance, and there are three types (type I, type II, and type III) based on their biological effects, receptor usage, and structure. Only type I and type III IFNs are directly produced in response to virus infection. Type I IFNs are key immune regulators essential for mounting a robust immune response to many viral infections (19,20). All subtypes of type I IFNs engage the ubiquitously expressed IFNAR and initiate a signaling cascade that leads to the induction of Ͼ300 IFN-stimulated genes (21). Type III IFNs include interleukin-28A (IL-28A), IL-28B, and IL-29 (also known as IFN-1, IFN-2, and IFN-3) (22, 23) and signal through the IFN-receptor (IFNLR) that is composed of an exclusive IFN-R1 chain and a shared IL-10R2 chain (23). Despite the low amino acid homology between type I and type III IFNs, they trigger common signaling pathways and biological activities (24,25). This functional redundancy is contested by the different receptor distributions and by the differential regulation of type I and type III IFN production during infection. Although IFNAR is present in all cells, the expression of IFNLR is limited to epithelial cells (26,27). Type III IFNs are produced at higher levels and during longer times in the lung than type I IFNs during influenza virus infection (28). These differences are likely t...

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…and poly(I:C) with type I and III IFN (43,68). Thus, the type of IFN induced in response to infection appears to be cell-and/or virus-specific rather than a pan-epithelial intrinsic response.…”

“…2D, purple symbols). We also tested the response to the dsRNA analog poly(I:C), which causes robust induction of the type I IFN system in transformed and nontransformed cell lines (42,43). Unlike rotavirus or other viruses (24,44), poly(I:C) does not antagonize IFN transcriptional responses.…”

Helicase proteins DHX29 and RIG-I cosense cytosolic nucleic acids in the human airway system

“…Recent studies demonstrated that in addition to providing a physical barrier, epithelia can sense viral infection. This ability is critical to subsequent activation of antiviral innate and adaptive immunity (2)(3)(4)(5)(6)(7)(8).…”

TLR3- and MyD88-Dependent Signaling Differentially Influences the Development of West Nile Virus-Specific B Cell Responses in Mice following Immunization with RepliVAX WN, a Single-Cycle Flavivirus Vaccine Candidate

“…Subsequently, inflammatory cytokines are released (9), and innate immune cells, including dendritic cells (10), are activated and play an important role in shaping humoral immunity (11). The double-stranded and single-stranded viral RNAs resulting from a WNV infection are recognized by TLR3 and TLR7/8, respectively.…”