scholarly journals Selective interferon responses of intestinal epithelial cells minimize TNFα cytotoxicity

2020 ◽  
Author(s):  
Jacob A. Van Winkle ◽  
David A. Constant ◽  
Lena Li ◽  
Timothy J. Nice
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Neonatal Mouse ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Type Iii ◽  
Apoptotic Genes ◽  
Type Iii Ifn

ABSTRACTInterferon (IFN) family cytokines stimulate genes (ISGs) that are integral to antiviral host defense. Type I IFNs act systemically whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, the response of IEC organoids to type I IFN is strikingly increased relative to type III IFN in magnitude and scope. The expanded type I IFN-specific response includes pro-apoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNFα). The ISGs stimulated in common by types I and III IFN have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including pro-apoptotic genes, have weak ISRE motifs. Thus, preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis.

scholarly journals Differential induction of interferon stimulated genes between type I andtype III interferons is independent of interferon receptor abundance

2018 ◽  
Author(s):  
Kalliopi Pervolaraki ◽  
Soheil Rastgou Talemi ◽  
Dorothee Albrecht ◽  
Felix Bormann ◽  
Connor Bamford ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Target Cells ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Type Iii ◽  
Interferon Stimulated Genes ◽  
Human Intestinal Epithelial Cells ◽  
Type Iii Ifn

AbstractIt is currently believed that type I and III interferons (IFNs) have redundant functions. However, the preferential distribution of type III IFN receptor on epithelial cells suggests functional differences at epithelial surfaces. Here, using human intestinal epithelial cells we could show that although both type I and type III IFNs confer an antiviral state to the cells, they do so with distinct kinetics. Type I IFN signaling is characterized by an acute strong induction of interferon stimulated genes (ISGs) and confers fast antiviral protection. On the contrary, the slow acting type III IFN mediated antiviral protection is characterized by a weaker induction of ISGs in a delayed manner compared to type I IFN. Moreover, while transcript profiling revealed that both IFNs induced a similar set of ISGs, their temporal expression strictly depended on the IFNs, thereby leading to unique antiviral environments. Using a combination of data-driven mathematical modeling and experimental validation, we addressed the molecular reason for this differential kinetic of ISG expression. We could demonstrate that these kinetic differences are intrinsic to each signaling pathway and not due to different expression levels of the corresponding IFN receptors. We report that type III IFN is specifically tailored to act in specific cell types not only due to the restriction of its receptor but also by providing target cells with a distinct antiviral environment compared to type I IFN. We propose that this specific environment is key at surfaces that are often challenged with the extracellular environment.Author summaryThe human intestinal tract plays two important roles in the body: first it is responsible for nutrient absorption and second it is the primary barrier which protects the human body from the outside environment. This complex tissue is constantly exposed to commensal bacteria and is often exposed to both bacterial and viral pathogens. To protect itself, the gut produces, among others, secreted agents called interferons which help to fight against pathogen attacks. There are several varieties (type I, II, and III) of interferons and our work aims at understanding how type I and III interferon act to protect human intestinal epithelial cells (hIECs) during viral infection. In this study, we confirmed that both interferons can protect hIECs against viral infection but with different kinetics. We determined that type I confer an antiviral state to hIECs faster than type III interferons. We uncovered that these differences were intrinsic to each pathway and not the result of differential abundance of the respective interferon receptors. The results of this study suggest that type III interferon may provide a different antiviral environment to the epithelium target cells which is likely critical for maintaining gut homeostasis. Our findings will also help us to design therapies to aid in controlling and eliminating viral infections of the gut.

scholarly journals Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Jacob A. Van Winkle ◽  
David A. Constant ◽  
Lena Li ◽  
Timothy J. Nice
Keyword(s):  
Specific Response ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Necrosis Factor Alpha ◽  
Type Iii ◽  
Factor Alpha ◽  
Type Iii Ifn ◽  
Necrosis Factor

ABSTRACT Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits the replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, IEC organoids have increased expression of the type I IFN receptor relative to neonate IECs, and the response of IEC organoids to type I IFN is strikingly increased in magnitude and scope relative to type III IFN. The expanded type I IFN-specific response includes proapoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNF-α). The ISGs stimulated in common by type I and III IFNs have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including proapoptotic genes, have weak ISRE motifs. Thus, the preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis. IMPORTANCE Enteric viral infections are a major cause of gastroenteritis worldwide and have the potential to trigger or exacerbate intestinal inflammatory diseases. Prior studies have identified specialized innate immune responses that are active in the intestinal epithelium following viral infection, but our understanding of the benefits of such an epithelium-specific response is incomplete. Here, we show that the intestinal epithelial antiviral response is programmed to enable protection while minimizing epithelial cytotoxicity that can often accompany an inflammatory response. Our findings offer new insight into the benefits of a tailored innate immune response at the intestinal barrier and suggest how dysregulation of this response could promote inflammatory disease.

scholarly journals Rotavirus NSP1 Inhibits Type I and Type III Interferon Induction

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 589
Author(s):  
Gennaro Iaconis ◽  
Ben Jackson ◽  
Kay Childs ◽  
Mark Boyce ◽  
Stephen Goodbourn ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Viral Gene Expression ◽  
Type I Interferons ◽  
Viral Gene ◽  
Type I ◽  
Type I Ifn ◽  
Viral Immunity ◽  
Type Iii ◽  
Type Iii Ifn

Type I interferons (IFNs) are produced by most cells in response to virus infection and stimulate a program of anti-viral gene expression in neighboring cells to suppress virus replication. Type III IFNs have similar properties, however their effects are limited to epithelial cells at mucosal surfaces due to restricted expression of the type III IFN receptor. Rotavirus (RV) replicates in intestinal epithelial cells that respond predominantly to type III IFNs, and it has been shown that type III rather than type I IFNs are important for controlling RV infections in vivo. The RV NSP1 protein antagonizes the host type I IFN response by targeting IRF-3, IRF-5, IRF-7, or β-TrCP for proteasome-mediated degradation in a strain-specific manner. Here we provide the first demonstration that NSP1 proteins from several human and animal RV strains antagonize type III as well as type I IFN induction. We also show that NSP1 is a potent inhibitor of IRF-1, a previously undescribed property of NSP1 which is conserved among human and animal RVs. Interestingly, all NSP1 proteins were substantially more effective inhibitors of IRF-1 than either IRF-3 or IRF-7 which has significance for evasion of basal anti-viral immunity and type III IFN induction in the intestinal epithelium.

scholarly journals Increased sensitivity of SARS-CoV-2 to type III interferon in human intestinal epithelial cells

2021 ◽  
Author(s):  
Carmon Kee ◽  
Camila Metz-Zumaran ◽  
Patricio Doldan ◽  
Cuncai Guo ◽  
Megan Stanifer ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Type I ◽  
Intestinal Epithelial ◽  
Human Intestine ◽  
Virus Spread ◽  
Type Iii ◽  
Type I Ifns ◽  
Human Intestinal Epithelial Cells ◽  
Type Iii Ifn

The coronavirus SARS-CoV-2 caused the COVID-19 global pandemic leading to 3.5 million deaths worldwide as of June 2021. The human intestine was found to be a major viral target which could have a strong impact on virus spread and pathogenesis since it is one of the largest organs. While type I interferons (IFNs) are key cytokines acting against systemic virus spread, in the human intestine type III IFNs play a major role by restricting virus infection and dissemination without disturbing homeostasis. Recent studies showed that both type I and III IFNs can inhibit SARS-CoV-2 infection, but it is not clear if one IFN controls SARS-CoV-2 infection of the human intestine better or with a faster kinetics. In this study, we could show that both type I and III IFNs possess antiviral activity against SARS-CoV-2 in human intestinal epithelial cells (hIECs), however type III IFN is more potent. Shorter type III IFN pretreatment times and lower concentrations were required to efficiently reduce virus load when compared to type I IFNs. Moreover, type III IFNs significantly inhibited SARS-CoV-2 even 4 hours post-infection and induced a long-lasting antiviral effect in hIECs. Importantly, the sensitivity of SARS-CoV-2 to type III IFNs was virus-specific since type III IFN did not control VSV infection as efficiently. Together these results suggest that type III IFNs have a higher potential for IFN-based treatment of SARS-CoV-2 intestinal infection as compared to type I IFNs.

scholarly journals Type III Interferon Restriction by Porcine Epidemic Diarrhea Virus and the Role of Viral Protein nsp1 in IRF1 Signaling

2017 ◽  
pp. JVI.01677-17 ◽  
Author(s):  
Qingzhan Zhang ◽  
Hanzhong Ke ◽  
Anthony Blikslager ◽  
Takashi Fujita ◽  
Dongwan Yoo
Keyword(s):  
Epithelial Cells ◽  
Porcine Epidemic Diarrhea Virus ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Cell Model ◽  
Intestinal Epithelial ◽  
Diarrhea Virus ◽  
Type Iii ◽  
Porcine Epidemic Diarrhea ◽  
Type Iii Ifn

Type III interferons (IFN-λs) play a vital role to maintain the antiviral state of the mucosal epithelial surface in the gut, and in turn, enteric viruses may have evolved to evade the type III IFN responses during infection. To study of the possible immune evasion of porcine epidemic diarrhea virus (PEDV) from type III IFN response, a line of porcine intestinal epithelial cells was developed as a cell model for PEDV replication. IFN-λ1 and IFN-λ3 inhibited the PEDV replication, indicating the anti-PEDV activity of type III IFNs. Of the 21 PEDV proteins, nsp1, nsp3, nsp5, nsp8, nsp14, nsp15, nsp16, ORF3, E, M, and N were found to suppress the type III IFN activities, and the IRF1 signaling mediated the suppression. PEDV specifically inhibited IRF1 nuclear translocation. Peroxisome is the innate antiviral signaling platform for activation of IRF1-mediated IFN-λ production, and peroxisomes were found to decrease in number in PEDV-infected cells. PEDV nsp1 blocked the nuclear translocation of IRF1 and reduced the number of peroxisomes to suppress IRF1-mediated type III IFNs. Mutational studies showed the conserved residues of nsp1 were crucial for IRF1-mediated IFN-λ suppression. Our study for the first time provides the evidence that the porcine enteric virus PEDV downregulates and evades the IRF1-mediated type III IFN responses by reducing the peroxisomes.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus emerged in swine in the US and has caused severe economic losses. PEDV targets the intestinal epithelial cells in the gut, and intestinal epithelial cells selectively induce and respond to the production of type III interferons (IFNs). However, little is known about modulation of type III IFN response by PEDV in the intestinal epithelial cells. In this study, we established a porcine intestinal epithelial cell model for PEDV replication. We found that PEDV inhibited the IRF1-mediated type III IFN production by decreasing the peroxisomes in number in the porcine intestinal epithelial cells. We also demonstrated that the conserved residues in the PEDV nsp1 protein were crucial for IFN suppression. This study for the first time showed the PEDV evasion of type III IFN response in the intestinal epithelial cells. It provides valuable information on the host cell-virus interactions not only for PEDV but also other enteric viral infections in swine.

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

2020 ◽  
Author(s):  
Megan L. Stanifer ◽  
Carmon Kee ◽  
Mirko Cortese ◽  
Sergio Triana ◽  
Markus Mukenhirn ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
De Novo ◽  
Intestinal Epithelial Cells ◽  
Critical Role ◽  
Type I ◽  
Intestinal Epithelial ◽  
Virus Particles ◽  
Type Iii ◽  
Human Intestinal Epithelial Cells ◽  
Type Iii Interferon

SummarySARS-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.

scholarly journals A host cell long noncoding RNA NR_033736 regulates type I interferon-mediated gene transcription and modulates intestinal epithelial anti-Cryptosporidium defense

2021 ◽  
Vol 17 (1) ◽  
pp. e1009241
Author(s):  
Juan Li ◽  
Kehua Jin ◽  
Min Li ◽  
Nicholas W. Mathy ◽  
Ai-Yu Gong ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Host Cell ◽  
Gene Transcription ◽  
Intestinal Epithelial Cells ◽  
Immune Defense ◽  
Fine Tuning ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type I Ifn ◽  
Innate Defense

The gastrointestinal epithelium guides the immune system to differentiate between commensal and pathogenic microbiota, which relies on intimate links with the type I IFN signal pathway. Epithelial cells along the epithelium provide the front line of host defense against pathogen infection in the gastrointestinal tract. Increasing evidence supports the regulatory potential of long noncoding RNAs (lncRNAs) in immune defense but their role in regulating intestinal epithelial antimicrobial responses is still unclear. Cryptosporidium, a protozoan parasite that infects intestinal epithelial cells, is an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children in developing countries. Recent advances in Cryptosporidium research have revealed a strong type I IFN response in infected intestinal epithelial cells. We previously identified a panel of host cell lncRNAs that are upregulated in murine intestinal epithelial cells following microbial challenge. One of these lncRNAs, NR_033736, is upregulated in intestinal epithelial cells following Cryptosporidium infection and displays a significant suppressive effect on type I IFN-controlled gene transcription in infected host cells. NR_033736 can be assembled into the ISGF3 complex and suppresses type I IFN-mediated gene transcription. Interestingly, upregulation of NR_033736 itself is triggered by the type I IFN signaling. Moreover, NR_033736 modulates epithelial anti-Cryptosporidium defense. Our data suggest that upregulation of NR_033736 provides negative feedback regulation of type I IFN signaling through suppression of type I IFN-controlled gene transcription, and consequently, contributing to fine-tuning of epithelial innate defense against microbial infection.

scholarly journals Importance of Type I and III Interferons at Respiratory and Intestinal Barrier Surfaces

2020 ◽  
Vol 11 ◽  
Author(s):  
Megan L. Stanifer ◽  
Cuncai Guo ◽  
Patricio Doldan ◽  
Steeve Boulant
Keyword(s):  
Epithelial Cells ◽  
Intestinal Barrier ◽  
The Body ◽  
Type I ◽  
Type I Ifn ◽  
Type Iii ◽  
Interferon Stimulated Genes ◽  
Mucosal Surfaces ◽  
Microbial Infections ◽  
Type Iii Ifn

Interferons (IFNs) constitute the first line of defense against microbial infections particularly against viruses. They provide antiviral properties to cells by inducing the expression of hundreds of genes known as interferon-stimulated genes (ISGs). The two most important IFNs that can be produced by virtually all cells in the body during intrinsic innate immune response belong to two distinct families: the type I and type III IFNs. The type I IFN receptor is ubiquitously expressed whereas the type III IFN receptor’s expression is limited to epithelial cells and a subset of immune cells. While originally considered to be redundant, type III IFNs have now been shown to play a unique role in protecting mucosal surfaces against pathogen challenges. The mucosal specific functions of type III IFN do not solely rely on the restricted epithelial expression of its receptor but also on the distinct means by which type III IFN mediates its anti-pathogen functions compared to the type I IFN. In this review we first provide a general overview on IFNs and present the similarities and differences in the signal transduction pathways leading to the expression of either type I or type III IFNs. By highlighting the current state-of-knowledge of the two archetypical mucosal surfaces (e.g. the respiratory and intestinal epitheliums), we present the differences in the signaling cascades used by type I and type III IFNs to uniquely induce the expression of ISGs. We then discuss in detail the role of each IFN in controlling pathogen infections in intestinal and respiratory epithelial cells. Finally, we provide our perspective on novel concepts in the field of IFN (stochasticity, response heterogeneity, cellular polarization/differentiation and tissue microenvironment) that we believe have implications in driving the differences between type I and III IFNs and could explain the preferences for type III IFNs at mucosal surfaces.

scholarly journals Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells—A Strategy Used by Coxsackie B Virus to Evade the Host’s Innate Immune Response at the Primary Site of Infection?

2021 ◽  
Vol 9 (1) ◽  
pp. 105
Author(s):  
Virginia M. Stone ◽  
Emma E. Ringqvist ◽  
Pär G. Larsson ◽  
Erna Domsgen ◽  
Ulrika Holmlund ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Protein Translation ◽  
Primary Site ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Type I ◽  
Intestinal Epithelial ◽  
Type Iii

Increasing evidence highlights the importance of the antiviral activities of the type III interferons (IFNλs; IL-28A, IL-28B, IL29, and IFNλ4) in the intestine. However, many viruses have developed strategies to counteract these defense mechanisms by preventing the production of IFNs. Here we use infection models, a clinical virus isolate, and several molecular biology techniques to demonstrate that both type I and III IFNs induce an antiviral state and attenuate Coxsackievirus group B (CVB) replication in human intestinal epithelial cells (IECs). While treatment of IECs with a viral mimic (poly (I:C)) induced a robust expression of both type I and III IFNs, no such up-regulation was observed after CVB infection. The blunted IFN response was paralleled by a reduction in the abundance of proteins involved in the induction of interferon gene transcription, including TIR-domain-containing adapter-inducing interferon-β (TRIF), mitochondrial antiviral-signaling protein (MAVS), and the global protein translation initiator eukaryotic translation initiation factor 4G (eIF4G). Taken together, this study highlights a potent anti-Coxsackieviral effect of both type I and III IFNs in cells located at the primary site of infection. Furthermore, we show for the first time that the production of type I and III IFNs in IECs is blocked by CVBs. These findings suggest that CVBs evade the host immune response in order to successfully infect the intestine.

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

2010 ◽  
Vol 84 (11) ◽  
pp. 5670-5677 ◽  
Author(s):  
Markus Mordstein ◽  
Eva Neugebauer ◽  
Vanessa Ditt ◽  
Birthe Jessen ◽  
Toni Rieger ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Respiratory Tract ◽  
Viral Infections ◽  
Influenza B Virus ◽  
Influenza B ◽  
Type I ◽  
Type I Ifn ◽  
Sars Coronavirus ◽  
Type Iii ◽  
Type Iii Ifn

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-α, IFN-β, and other type I IFN molecules signal through a common, universally expressed cell surface receptor, whereas type III IFN (IFN-λ) uses a distinct cell-type-specific receptor complex for signaling. Using mice lacking functional receptors for type I IFN, type III IFN, or both, we found that IFN-λ 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-λ receptor defect. Careful analysis revealed that expression of functional IFN-λ 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-λ contributes to the control of viral infections in epithelial cells of both respiratory and gastrointestinal tracts.

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