PRRs, such as Toll-like receptors (TLRs), recognize common features of microorganisms, thus providing them with a strategy to detect diverse and unrelated pathogens [21]. You may notice problems with Studies have shown that primary murine tracheal respiratory epithelial cells and murine lung epithelial cell lines are able to respond to both type I and III IFN [36,37]. Another in vivo study also showed that recombinant IFN-λ2 treatment of pregnant dams restricted the vertical transmission of ZIKV [73]. the display of certain parts of an article in other eReaders. The SYN is a highly unique cell type given that it does not contain any cellular junctions and instead exists as a large syncytium of shared cytosolic space and multiple nuclei. These studies have shown that IFN-λ has an important role at the GI epithelium; however, immortalized cell lines are often derived from malignancies, in which native healthy cell signaling pathways are inherently altered and therefore, these cell lines do not fully recapitulate the diversity of cell types present in the epithelium or their functionality. Collectively, these defensive strategies work in concert to directly clear pathogens (e.g. Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor that consists of IFNAR1 and IFNAR2 chains. Each IFN-λ gene has 5 exons; this characteristic shares homology with the IL-10 cytokine family [15]. Consistent with a possible autocrine feedback of released IFN-λs on the placenta itself, isolated placental trophoblasts from full-term placentas and explants of mid-gestation chorionic villi expressed high levels of ISGs under basal (uninfected) states, suggesting that released IFN-λ might function to protect the placenta from viral infections [67,68]. In this review, we focus on the role of IFN-λ at barrier surfaces, focusing on the respiratory and GI tracts, the BBB, and the placenta and how these IFNs act to suppress viral infections. Utilizing a mouse model wherein the fetal-derived placenta lacks functional IFN-λ signaling in the setting of an IFN-λ competent pregnant dam, a recent study investigated whether type III IFNs protected against transplacental ZIKV transmission [72]. Syncytiotrophoblasts form a dense brush border, but unlike the respiratory and GI epithelium, does not contain junctional complexes between cells (as the syncytium is a continuous layer). The cell composition of the blood-brain barrier, respiratory tract, gastrointestinal tract, and placenta are shown. Do defects in IFN-λ signaling sensitize the fetus to viral infections? Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Accordingly, JEG-3 cultured in 3-D become resistant to infection by viruses (vesicular stomatitis virus (VSV) and ZIKV) and conditioned medium isolated from these cells has been shown to induce ISGs and to confer protection from ZIKV infection in non-placental cells responding to type III IFNs [68,71]. Historically, the role of IFNs in the GI tract has mostly been studied in the context of cell lines [44]. [1] They were discovered in 2003. For instance, mice lacking functional type III IFN signaling (Ifnlr1−/−) exhibit increased BBB permeability and higher viral titers after WNV infection relative to wild type controls [57]. Cells that have been infected with a virus produce interferon, which sends a signal to other cells of the body to resist viral growth. The family of type I IFN comprises more than 20 members with multiple IFN-α ⦠Unlike the canonical mechanism of IFN-induced antiviral defenses through ISG induction, type III IFNs also function to protect mice from WNV infection through non-ISG-dependent mechanisms. Similar findings have been shown in the context of RSV infection [41]. Interferons and Lymphoid Organs are part of the Immune System of the human body. Collectively, these studies indicate that IFN-λ is an important mediator of antiviral defenses in the respiratory tract. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. IFN-λ4 has been shown to induce antiviral activity against hepatitis C virus in cultured Huh7 liver cells [12]. Collectively, human and mouse studies have provided insights into IFN-λ signaling at the maternal-fetal interface and suggest that placental trophoblasts are key cellular components in this process. Recombinant IFN-λ treatment is protective against vertical transmission of Zika virus in vivo. already built in. However, whereas type I IFNs control infection systemically, type III IFNs (IFN-λs) control infection locally at barrier surfaces and are often preferentially induced by these cells. Trends Immunol. The induction of each class of IFNs has been shown to require slightly different proteins to bind to the promoter of a given gene [22]. Interferons are proteins made by cells in response to infection. Indeed, a recent study showed that mouse placentas derived from mouse fetuses expressing a single copy of IFNAR (Ifnar+/−) were resorbed at much higher rates than littermates homozygously lacking type I IFN signaling (Ifnar−/−) when dams were infected intravaginally with ZIKV [74]. Neutrophils are one of the few immune cells that express IFNLR and can respond to IFN-λ, representing an important bridge between innate and adaptive immunity [19,20]. Initially, IFNλ was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. Interferons are proteinaceous in nature. Thus, although the precise cellular targets of placental-derived IFN-λ remain unclear, several pieces of evidence indicate that both maternal- and fetal-derived tissues are likely to benefit from its protective effects during pregnancy. Instead, fetal demise resulted from hypoxia and reabsorption, suggesting adverse impacts on placental function [74]. Type I IFNs are located on chromosome 9 in humans and on chromosome 4 in mice [6]. However, given that the GI epithelium is composed of multiple cell types, it remains unclear whether type I and III IFNs function equivalently in these cell types, or whether cell type specificity governs their functions. In addition to their role as physical barriers, it is becoming increasingly clear that the cell types comprising barriers in the human body are also dynamic and highly reactive chemical barriers that use type III IFNs to protect these sites from viral infections. Cells infected with viruses secrete interferons that travel to adjacent cells and induce them to make antiviral proteins. Interferons (IFNs) are key cytokines produced during innate immune detection of viral infections. Whereas type III IFNs promote antiviral defenses, which might protect the fetus and placenta from certain viral infections, the activity of type I IFNs appears to exert an opposing effect, with these types of IFNs damaging placental structure and function. Human type I interferons (IFNs) are a large subgroup of interferon proteins that help regulate the activity of the immune system. The different modes of barrier defenses are associated with the external surfaces of the body, where pathogens may try to enter (Table). viruses) from the lungs or to prevent their penetration into the bloodstream should they bypass other physical defenses. In contrast, when pregnant dams were infected later in gestation (following complete placental development at ~E9.5), only placentas lacking functional type III IFN signaling displayed high rates of ZIKV vertical transmission, which correlated with high fetal viral loads, fetal demise, and/or congenital malformations. These shared mechanisms include goblet cell-derived mucus secretions in the GI and respiratory tracts, which coat the cell surface with a protective barrier, the formation of junctional complexes limiting paracellular transport, and the formation of complex apical actin networks that limit direct passage of molecules across the cell surface, amongst others [2,3]. However, although human intestinal organoids induce the expression of both type I and III IFNs at the transcript level in response to rotavirus infections, only type III IFNs are secreted from infected cells [53,54], suggesting that the GI epithelial cells are preferentially secreting type III IFNs over type I IFNs. In humans, type I IFN is located in an intron-less region of the chromosome where the alpha subtypes are located on the 3’ end, with IFN-β on the 5’ end of the locus [7,8]. These results indicate that ISG induction by type I and III IFN is dependent on many factors, including IFN concentration, cell and tissue type, and time points assessed. In mice, type III IFNs are also preferentially induced by IAV infection [33] and mice deficient in IL28RA exhibit higher levels of IAV replication compared to wild type controls [43]. Extravillous trophoblasts (EVTs) reside at the tips of anchoring villi and imbed directly into the maternal decidua to anchor the fetal placenta to the uterus and are also responsible for remodeling the maternal microvasculature [1]. The barrier defenses are not a response to infections, but they are continuously working to protect against a broad range of pathogens. IFNs not only have important antiviral effects but also have a role in antitumor and immunomodulatory responses. Similar to polarized epithelial cells, the microvascular endothelial cells that comprise the BBB are connected by junctional complexes between adjacent cells. Of relevance, the expression of IFNs and ISGs in various cells can trigger a state of antiviral immunity, and here we focus on barrier surfaces. IFNs play a primary role in barrier defenses and are important for barrier function and ⦠As a service to our customers we are providing this early version of the manuscript. The epithelium forms a physical barrier in part due to the presence of tripartite junctional complexes (composed of tight and adherens junctions, and desmosomes) that form between neighboring cells to restrict the free flow of ions and solutes [31]. Generating an ePub file may take a long time, please be patient. We apologize to those whose work we did not cover in detail due to space restrictions. These barriers utilize nonredundant mechanisms to suppress viral infections including the production of interferons (IFNs), which induce a strong antiviral state following receptor binding. The respiratory epithelial cells have cilia which beat in concert to clear mucus. Beneath the endothelium is a continuous basement membrane that connects the microvasculature to the pericytes and endfoot astrocytes that further limit permeability of the barrier [56]. Interferons (IFNs) are central to antiviral immunity. Although these cells can respond to both types of IFNs, they preferentially induce type III IFNs in response to influenza A virus (IAV), respiratory syncytial virus (RSV), M. tuberculosis, and other viral infections [38–41]. Other studies have indicated that human stem cell-derived enteroids treated with either IFN-β or IFN-λ induce ISGs in a similar manner [30]. The blood-brain barrier is made up in part of microvascular endothelial cells which form a physical barrier between the brain and the blood. Placental trophoblasts constitutively releases type III IFNs as a mechanism to protect the placenta from viral infections. On the one hand, IRF7 does not typically bind to the promoter of IFNB in unstimulated cells, largely due to the fact that it is itself an ISG and must be upregulated before it can become fully expressed and activated. The physical barriers that comprise the respiratory epithelial barrier (described above) are largely shared by the GI epithelium, with the exception of beating cilia. The IVS contains as much as 150mL of maternal blood at the later stages of pregnancy, which is delivered by hundreds of maternal spiral arteries in the uterus [1]. Fetal derived syncytiotrophoblasts constitutively release IFN-λs that lead to the upregulation of ISGs in both autocrine (in the syncytium itself) and paracrine (presumably in maternal-derive tissue) manners. Overall, aside from sharing homology with the IL-10 cytokine family, type III IFNs share the IL-10R2 receptor subunit, leading to the speculation that these cytokines might be evolutionarily related [4,16]. The innate immune system is activated by the recognition of ‘non-self’ from ‘self’ through diverse pattern recognition receptors. However, unlike the canonical pathway of ISG induction, IFN-λ appears to exert its antiviral activity at least in part from a direct increase in endothelial barrier properties. human placental fibroblasts), or, upon RNAi mediated reduction of IFNLR expression in human brain microvascular endothelial cells [67,68]. This family includes IFN-λ1, IFN-λ2, and IFN-λ3, also known as interleukin IL-29, IL-28A, and IL-28B [9,10]. However, is it less clear what the paracrine-mediated impact of constitutive IFN-λ release could be in the context of pregnancy. Interferons (IFNs) are key cytokines produced during innate immune detection of viral infections. The role of type III IFNs in the human BBB are less clear, owing in part to the difficulties of modeling this complex system ex vivo. Subjacent to the SYN layer are cytotrophoblasts (CYTs), which are mononuclear cells that fuse through the activity of the endogenous retrovirus fusion protein syncytin/HERV-W to form the SYN [63]. Consistent with this, maternal-derived decidua tissue and fetal-derived amnion and chorion membranes and isolated epithelial cells are highly responsive to recombinant IFN-λ treatment, which suppresses ZIKV infection [72,73]. Another group of proteins that provide protection are the interferons, which inhibit the replication of manyâbut not allâviruses. It is important to note that the release of type III IFNs from placental trophoblasts is not conserved in human trophoblast cell lines, including BeWo, JEG-3, and JAR cells [67]. This space is highly contained and given this structure, it is possible that IFN-λ released from the placenta within this space remains localized and acts on key cells located at the maternal-fetal interface, rather than being transported systemically. Type I IFN was discovered in 1957 by Isaacs and Lindenmann, who named the factor because of its ability to interfere with viral replication [5]. In addition, these cell types have, in some cases, also co-evolved by sharing defensive strategies, despite their disparate locations throughout the body. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The phagocytes are the bodyâs fast acting, first line of immunological defense against organisms that have breached barrier defenses and have entered the vulnerable tissues of the body. IFNs play a primary role in barrier defenses and are important for barrier function and integrity in the face of viral infections. 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