Lambda Interferon Renders Epithelial Cells of the Respiratory and Gastrointestinal Tracts Resistant to Viral Infections

Abstract

Virus-infected cells secrete a broad range of interferons (IFN) which confer resistance to yet uninfected cells by triggering the synthesis of antiviral factors. The relative contributions of the various IFN subtypes to innate immunity against virus infections remain elusive. IFN-␣, IFN-␤, and other type I IFN molecules signal through a common, universally expressed cell surface receptor, whereas type III IFN (IFN-) uses a distinct cell-typespecific receptor complex for signaling. Using mice lacking functional receptors for type I IFN, type III IFN, or both, we found that IFN-plays an important role in the defense against several human pathogens that infect the respiratory tract, such as influenza A virus, influenza B virus, respiratory syncytial virus, human metapneumovirus, and severe acute respiratory syndrome (SARS) coronavirus. These viruses were more pathogenic and replicated to higher titers in the lungs of mice lacking both IFN receptors than in mice with single IFN receptor defects. In contrast, Lassa fever virus, which infects via the respiratory tract but primarily replicates in the liver, was not influenced by the IFN-receptor defect. Careful analysis revealed that expression of functional IFN-receptor complexes in the lung and intestinal tract is restricted to epithelial cells and a few other, undefined cell types. Interestingly, we found that SARS coronavirus was present in feces from infected mice lacking receptors for both type I and type III IFN but not in those from mice lacking single receptors, supporting the view that IFN-contributes to the control of viral infections in epithelial cells of both respiratory and gastrointestinal tracts.The interferon (IFN) system represents a major element of the innate immune response against viral infections (10,13,14). Virus-induced IFN is a complex mixture of biologically active molecules, which includes type I and type III IFN. Type I IFN consists of 14 different IFN-␣ subtypes in the mouse as well as IFN-␤, IFN-, IFN-ε, and limitin, which all signal through the same universally expressed cell surface receptor complex (IFNAR) (30). Type III IFN includes IFN-1, IFN-2, and IFN-3 (21, 28), of which only the latter two are encoded by genes that are expressed in the mouse (22). Type III IFN uses a distinct receptor complex (IL28R) for signaling (21, 28), which appears to be expressed on only a few cell types, including epithelial cells (29). Binding of type I IFN and type III IFN to their cognate receptor complexes triggers signaling cascades that result in the activation of a large number of genes, many of which encode antiviral proteins (10, 32). Type I IFN and type III IFN trigger highly similar gene expression profiles in responsive cells, suggesting that both IFN types might serve similar functions. However, it has to date been largely unclear to which extent IFN-might contribute to innate immunity.Using knockout mouse strains that lack receptors for type I IFN (IFNAR1 0/0 ), type III IFN (IL28R␣ 0/0 ), or both (IFNAR1 0/0 IL28R␣ 0/0 ), we have recently ...

Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses

“…Type III IFN has been shown to be the predominant IFN induced in vivo during influenza A virus infection (47). Indeed, in a comprehensive study in mice by Mordstein et al (48), type III IFN was shown to play a crucial role in protecting respiratory tract epithelial cells from infection with pneumotropic virus such as influenza A virus, influenza B virus, respiratory syncytial virus, human metapneumovirus, and severe acute respiratory syndrome coronavirus (48) (21) demonstrated N pro targets IRF7 for degradation in pDCs, leading to a reduction in type I IFN expression. However, in pDCs, constitutive expression of IRF7 allows IFN-a to be produced rapidly, and it may be the case that a level of IFN-a is produced by pDCs in response to BVDV infection prior to the action of the N pro protein.…”

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…IL-29 is a recently discovered cytokine that has similar mode of anti-viral activity as IFN-I (Dumoutier et al 2004;Meager et al 2005;Ank et al 2008;Uze and Monneron 2007). However, IFN-III seems to have a more specialized role in epithelial and mucosal antiviral defense (Brand et al 2005;Okabayashi et al 2011) since the expression of IFN-III receptor is restricted to renal and mucosal epithelial surfaces (Iversen et al 2010;Li et al 2009;Sommereyns et al 2008;Mordstein et al 2010). Except for one recent study from our laboratory reporting decreased IL-29 secretion by pDCs from aged, there is a scarcity of information regarding the status of IL-29 production during aging.…”

“…Recently discovered type III IFNs -IFN-III (IL28/29) -display type I IFNlike antiviral activity and induction of typical IFNinducible genes except that they provide better protection against viral infections at respiratory mucosal surfaces (Ank and Paludan 2009). It has been reported that IFN-III contributes greatly in defense against pathogens that infect respiratory tract such as Influenza A virus, influenza B virus, RSV which interestingly affect predominantly the elderly population (Jewell et al 2010;Mordstein et al 2008Mordstein et al , 2010. Unlike IFN-alpha receptors which are broadly expressed on most cell types, including leukocytes, IFN-lambda receptors are largely restricted to cells of epithelial origin which may explain their effectiveness against respiratory pathogens.…”

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

“…Increased pathogenicity of influenza virus in mice lacking both IFNAR and IFNLR was found compared with mice with single receptor defects [53]. An important antiviral role for the ISG expression of MxA has been elucidated requiring type I and type III IFN signaling pathways for induction [54]. Furthermore, IFN−β-knockout mice have also provided important information on the role of IFN−β and pDC function in respiratory infection with influenza virus.…”