Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology

Pott, Johanna; Stockinger, Silvia

doi:10.3389/fimmu.2017.00258

Cited by 54 publications

(50 citation statements)

References 140 publications

(244 reference statements)

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“…Therefore, it is possible that type III IFN may be the predominant IFN to mediate antiviral effects in the liver, while type I IFN may play an important role in enterocytes, the initial site of HEV replication. Interestingly, type III IFN is known to contribute to antiviral responses at the intestinal mucosal surface (30,31); however, in this study, we found that HEV RNA PAMPs induced higher type I IFN mRNA levels than type III IFN levels in enterocytes. Therefore, more in-depth in vivo studies are warranted to more definitively delineate the role of type I and type III IFNs at various target organs during HEV infection.…”

Section: Discussioncontrasting

confidence: 77%

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Sooryanarain

Heffron

Meng

2020

mBio

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Hepatitis E virus (HEV), a single-strand positive-sense RNA virus, is an understudied but important human pathogen. The virus can establish infection at a number of host tissues, including the small intestine and liver, causing acute and chronic hepatitis E as well as certain neurological disorders. The retinoic acid-inducible gene I (RIG-I) pathway is essential to induce the interferon (IFN) response during HEV infection. However, the pathogen-associated motif patterns (PAMPs) in the HEV genome that are recognized by RIG-I remain unknown. In this study, we first identified that HEV RNA PAMPs derived from the 3′ untranslated region (UTR) of the HEV genome induced higher levels of IFN mRNA, interferon regulatory factor-3 (IRF3) phosphorylation, and nuclear translocation than the 5′ UTR of HEV. We revealed that the U-rich region in the 3′ UTR of the HEV genome acts as a potent RIG-I PAMP, while the presence of poly(A) tail in the 3′ UTR further increases the potency. We further demonstrated that HEV UTR PAMPs induce differential type I and type III IFN responses in a cell type-dependent fashion. Predominant type III IFN response was observed in the liver tissues of pigs experimentally infected with HEV as well as in HEV RNA PAMP-induced human hepatocytes in vitro. In contrast, HEV RNA PAMPs induced a predominant type I IFN response in swine enterocytes. Taken together, the results from this study indicated that the IFN response during HEV infection depends both on viral RNA motifs and host target cell types. The results have important implications in understanding the mechanism of HEV pathogenesis. IMPORTANCE Hepatitis E virus (HEV) is an important human pathogen causing both acute and chronic viral hepatitis E infection. Currently, the mechanisms of HEV replication and pathogenesis remain poorly understood. The innate immune response acts as the first line of defense during viral infection. The retinoic acid-inducible gene I (RIG-I)-mediated interferon (IFN) response has been implicated in establishing antiviral response during HEV infection, although the HEV RNA motifs that are recognized by RIG-I are unknown. This study identified that the U-rich region in the 3′ untranslated region (UTR) of the HEV genome acts as a potent RIG-I agonist compared to the HEV 5′ UTR. We further revealed that the HEV RNA pathogen-associated motif patterns (PAMPs) induced a differential IFN response in a cell type-dependent manner: a predominantly type III IFN response in hepatocytes, and a predominantly type I IFN response in enterocytes. These data demonstrate the complexity by which both host and viral factors influence the IFN response during HEV infection.

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Section: Discussioncontrasting

confidence: 77%

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Sooryanarain

Heffron

Meng

2020

mBio

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“…While IFNLR1 expression has also been reported on NK cells, T cells, B cells, and pDCs (26)(27)(28)(29)(30), no role has been found for these cells in IFN-λ-mediated antiviral responses. Type I IFNs, on the other hand, are critical for preventing a virus from moving past this initial epithelial barrier into systemic tissues (24,25,31). The host may benefit by inducing specific and local barrier defenses at a site commonly exposed to pathogens via IFN-λ signaling, and thus avoid potentially detrimental systemic inflammatory responses by type I IFNs.…”

Section: Figure 1 | Effects Of Interferon-lambda (Ifn-λ) On Viruses Imentioning

confidence: 99%

Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections

Lee

Baldridge

2017

Front. Immunol.

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Interferon-lambda (IFN-λ) is a recently described cytokine found to be of critical importance in innate immune regulation of intestinal viruses. Endogenous IFN-λ has potent antiviral effects and has been shown to control multiple intestinal viruses and may represent a factor that contributes to human variability in response to infection. Importantly, recombinant IFN-λ has therapeutic potential against enteric viral infections, many of which lack other effective treatments. In this mini-review, we describe recent advances regarding IFN-λ-mediated regulation of enteric viruses with important clinical relevance including rotavirus, reovirus, and norovirus. We also briefly discuss IFN-λ interactions with other cytokines important in the intestine, and how IFN-λ may play a role in regulation of intestinal viruses by the commensal microbiome. Finally, we indicate currently outstanding questions regarding IFN-λ control of enteric infections that remain to be explored to enhance our understanding of this important immune molecule.

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“…Type I IFNs signal through the interferon alpha receptor (IFNAR) to activate the Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway to induce ISG transcription (9). Type III IFN, also known as interferon lambda (IFN-) or interleukin 28 (IL-28)/IL-29, binds to an IL-28 receptor alpha (IL-28R␣)/IL-10R␤ heterodimeric receptor (IFNLR) to activate the JAK-STAT pathway and plays an important role in antiviral immunity at mucosal surfaces, including the lung and gastrointestinal tract (10)(11)(12). Investigation of hostvirus interactions has uncovered critical roles for both type I and type III IFNs in the regulation of acute and persistent strains of MNoV (5,7,13,14).…”

mentioning

confidence: 99%

HOIL1 Is Essential for the Induction of Type I and III Interferons by MDA5 and Regulates Persistent Murine Norovirus Infection

MacDuff

Baldridge

Qaqish

et al. 2018

J Virol

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The linear ubiquitin chain assembly complex (LUBAC), composed of heme-oxidized IRP2 ubiquitin ligase 1 (HOIL1), HOIL1-interacting protein (HOIP), and SHANK-associated RH domain-interacting protein (SHARPIN), is a crucial regulator of multiple immune signaling pathways. In humans, HOIL1 or HOIP deficiency is associated with an immune disorder involving autoinflammation, immunodeficiency, and inflammatory bowel disease (IBD)-like symptoms. During viral infection, LUBAC is reported to inhibit the induction of interferon (IFN) by the cytosolic RNA sensor retinoic acid-inducible gene I (RIG-I). Surprisingly, we found that HOIL1 is essential for the induction of both type I and type III IFNs, as well as the phosphorylation of IFN regulatory factor 3 (IRF3), during murine norovirus (MNoV) infection in cultured dendritic cells. The RIG-I-like receptor, melanoma differentiation-associated protein 5 (MDA5), is also required for IFN induction and IRF3 phosphorylation during MNoV infection. Furthermore, HOIL1 and MDA5 were required for IFN induction after Theiler's murine encephalomyelitis virus infection and poly(I·C) transfection, but not Sendai virus or vesicular stomatitis virus infection, indicating that HOIL1 and LUBAC are required selectively for MDA5 signaling. Moreover, mice exhibited defective control of acute and persistent murine norovirus infection and defective regulation of MNoV persistence by the microbiome as also observed previously for mice deficient in interferon lambda (IFN-λ) receptor, signal transducer and activator of transcription factor 1 (STAT1), and IRF3. These data indicate that LUBAC plays a critical role in IFN induction to control RNA viruses sensed by MDA5. Human noroviruses are a leading cause of gastroenteritis throughout the world but are challenging to study and Murine norovirus (MNoV) provides a tractable genetic and small-animal model to study norovirus biology and immune responses. Interferons are critical mediators of antiviral immunity, but excessive expression can dysregulate the immune system. IFN-λ plays an important role at mucosal surfaces, including the gastrointestinal tract, and both IFN-λ and commensal enteric bacteria are important modulators of persistent MNoV infection. LUBAC, of which HOIL1 is a component, is reported to inhibit type I IFN induction after RIG-I stimulation. We show, in contrast, that HOIL1 is critical for type I and III IFN induction during infection with MNoV, a virus that preferentially activates MDA5. Moreover, HOIL1 regulates MNoV infection These data reveal distinct functions for LUBAC in these closely related signaling pathways and in modulation of IFN expression.

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Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology

Cited by 54 publications

References 140 publications

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner

Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections

HOIL1 Is Essential for the Induction of Type I and III Interferons by MDA5 and Regulates Persistent Murine Norovirus Infection

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