Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance

Pervolaraki, Kalliopi; Talemi, Soheil Rastgou; Albrecht, Dorothee; Bormann, Felix; Bamford, Connor; Mendoza, Juan L.; García, K. Christopher; McLauchlan, John; Höfer, Thomas; Stanifer, Megan L.; Boulant, Steeve

doi:10.1371/journal.ppat.1007420

Cited by 108 publications

(130 citation statements)

References 71 publications

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“…Interestingly, in human colon organoids we observed that only type III IFN is made upon SARS-CoV-2 infection, although human intestinal organoids are capable of making both type I and III IFN upon enteric virus infection (Pervolaraki et al, 2018;Stanifer et al, 2020). The lack of type I induction appears to be specific to SARS-CoV-2 and it is likely that this virus encodes a specific antagonist which counteracts the production of type I IFN only.…”

Section: Discussionmentioning

confidence: 77%

“…The reason for the difference in the amount of IFN made upon infection of lung vs. intestinal epithelial cells is currently unclear. Like intestinal epithelial cells(Pervolaraki et al, 2017(Pervolaraki et al, , 2018Pott et al, 2011), lung epithelial cells are normally highly immunoresponsive and make IFNs upon viral infection(Crotta et al, 2013;Ye et al, 2019). The lack of IFN in lung epithelial cells following SARS-CoV-2 infection might be specific for this virus in this tissue(Blanco-Melo et al, 2020) as SARS-CoV-1 induces IFN production in infected lung tissue(Chu et al).…”

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confidence: 99%

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Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Stanifer

Kee

Cortese

et al. 2020

Preprint

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SARS-CoV-2 is an unprecedented worldwide health problem that requires concerted and global approaches to better understand the virus in order to develop novel therapeutic approaches to stop the COVID-19 pandemic and to better prepare against potential future emergence of novel pandemic viruses. Although SARS-CoV-2 primarily targets cells of the lung epithelium causing respiratory infection and pathologies, there is growing evidence that the intestinal epithelium is also infected. However, the importance of the enteric phase of SARS-CoV-2 for virus-induced pathologies, spreading and prognosis remains unknown.Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of SARS-CoV-2 lifecycle in human intestinal epithelial cells. Our results demonstrate that human intestinal epithelial cells fully support SARS-CoV-2 infection, replication and production of infectious de-novo virus particles. Importantly, we identified intestinal epithelial cells as the best culture model to propagate SARS-CoV-2. We found that viral infection elicited an extremely robust intrinsic immune response where, interestingly, type III interferon mediated response was significantly more efficient at controlling SARS-CoV-2 replication and spread compared to type I interferon.Taken together, our data demonstrate that human intestinal epithelial cells are a productive site of SARS-CoV-2 replication and suggest that the enteric phase of SARS-CoV-2 may participate in the pathologies observed in COVID-19 patients by contributing in increasing patient viremia and by fueling an exacerbated cytokine response.

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Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 99%

Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Stanifer

Kee

Cortese

et al. 2020

Preprint

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“…We also revealed that HEV UTR PAMPs induce type I and type III IFN responses in a cell type-dependent fashion. Studies have shown that various IFN subtypes exert different spatial and temporal activation kinetic patterns in vivo (33) and also use distinct mechanisms to establish antiviral states in vitro (34). Therefore, the complexity of virus-host interactions modulates the expression of various IFN subtypes and, in turn, controls the antiviral response kinetics at a given target organ.…”

Section: Discussionmentioning

confidence: 99%

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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“…This is in agreement with a paper recently published showing that ISGs can be grouped into four groups, those that are induced within 3 hours, 6 hours, 12 hours or take 24 hours. IFITM3 was within the 24 hour group, at which point the experiment was stopped (25). This delay in IFITM3 expression following IFN induction further increases the risk of infection in cells with low IFITM3 basal expression, even if they can then induce IFITM3 following IFN stimulation.…”

Section: Discussionmentioning

confidence: 99%

Low basal expression and slow induction of IFITM3 puts immune cells at risk of influenza A infection

Wellington

Yin

Zhang

et al. 2019

Preprint

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The interferon-induced transmembrane protein, IFITM3, has been shown to restrict influenza virus infection in murine and in vitro settings for ten years, but no explanation has been found to explain why this virus infection is so highly contagious and infects most individuals it comes in contact with. We confirm that the expression level of IFITM3 plays a role in determining the level of viral infection through manipulation of IFITM3 levels with interferon (IFN) stimulation and overexpression systems. Low basal expression may put some immune cells, including lymphocytes and lung-resident macrophages, at risk of influenza virus infection. Investigating the induction of IFITM3 by IFN, we find a strong preference for Type I IFN in IFITM3 induction in both cell lines and primary human cells. While myeloid cells can increase expression following stimulation by Type I IFN, lymphocytes show minimal induction of IFITM3 following IFN stimulation, suggesting that they are always at risk of viral infection. Surprisingly, we found that the time it takes for maximal induction of IFITM3 is relatively slow for an interferon-stimulated gene at around 36 hours. Low basal expression and slow induction of IFITM3 could increase the risk of influenza virus infection in selected immune cells.ImportanceInfluenza virus infection remains one of the top ten threats to global health, causing significant deaths and hospitalisations across the world each year. Understanding mechanisms for controlling influenza virus infection remain a priority. The interferon-induced transmembrane protein IFITM3 can restrict influenza infection by limiting replication of the virus. The precise mechanisms of how IFITM3 reduced replication of influenza are unknown, although it is predicted to prevent release of viral contents into the cytosol by preventing pore formation on the endosomal compartments where it is suggested to reside. Here we have shown that the expression level of IFITM3 is important in determining the control of influenza virus infection. We find an expression pattern for IFITM3 that varies based on cell type, tissue locality, differentiation state and cell naivety, all of which highlights cells that may be at the highest risk of influenza infection.

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Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance

Cited by 108 publications

References 71 publications

Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

Critical role of type III interferon in controlling SARS-CoV-2 infection, replication and spread in primary human intestinal epithelial cells

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

Low basal expression and slow induction of IFITM3 puts immune cells at risk of influenza A infection

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