Rotavirus NSP1 Inhibits Type I and Type III Interferon Induction

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.

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Selective interferon responses of intestinal epithelial cells minimize TNFα cytotoxicity

10.1101/2020.03.20.000604 ◽

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2020.608645 ◽

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.

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

Journal of Virology ◽

10.1128/jvi.00603-20 ◽

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.

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

10.1101/448357 ◽

2018 ◽

Cited By ~ 1

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.

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

Journal of Virology ◽

10.1128/jvi.00272-10 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5670-5677 ◽

Cited By ~ 243

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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Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats

Journal of General Virology ◽

10.1099/vir.0.83294-0 ◽

2008 ◽

Vol 89 (1) ◽

pp. 261-270 ◽

Cited By ~ 30

Author(s):

Lioubov M. Pletneva ◽

Otto Haller ◽

David D. Porter ◽

Gregory A. Prince ◽

Jorge C. G. Blanco

Keyword(s):

Gene Expression ◽

Respiratory Syncytial Virus ◽

Virus Replication ◽

Surrogate Marker ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Type I Ifn ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis in young children. In general, RSV is considered to be a poor inducer of type I (alpha/beta) interferons (IFNs). Measurement of active type I IFN production during infection in vivo is demanding, as multiple IFN subtypes with overlapping activities are produced. In contrast, Mx gene expression, which is tightly regulated by type I IFN expression, is easily determined. This study therefore measured Mx expression as a reliable surrogate marker of type I IFN activity during RSV infection in vivo in a cotton rat model. It was shown that expression of Mx genes was dramatically augmented in the lungs of infected animals in a dose- and virus strain-dependent manner. The expression of Mx genes in the lungs was paralleled by their induction in the nose and spleen, although in spleen no simultaneous virus gene expression was detected. Reinfection of RSV-immune animals leads to abortive virus replication in the lungs. Thus, type I IFN and Mx gene expression was triggered in reinfected animals, even though virus could not be isolated from their lungs. Furthermore, it was demonstrated that immunity to RSV wanes with time. Virus replication and Mx gene expression became more prominent with increasing intervals between primary infection and reinfection. These results highlight the role of type I IFN in modulation of the immune response to RSV.

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Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Blood ◽

10.1182/blood.v99.9.3263 ◽

2002 ◽

Vol 99 (9) ◽

pp. 3263-3271 ◽

Cited By ~ 332

Author(s):

Maria Montoya ◽

Giovanna Schiavoni ◽

Fabrizio Mattei ◽

Ion Gresser ◽

Filippo Belardelli ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

T Cell ◽

Bone Marrow Cells ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Type I Ifns

Abstract Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-α and IFN-β, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti–IFN-α/β antibody to purified splenic DCs in vitro partially blocked the “spontaneous” activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-γ, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

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Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

eLife ◽

10.7554/elife.67290 ◽

2021 ◽

Vol 10 ◽

Author(s):

Daisy X Ji ◽

Kristen C Witt ◽

Dmitri I Kotov ◽

Shally R Margolis ◽

Alexander Louie ◽

...

Keyword(s):

Legionella Pneumophila ◽

Bacterial Infections ◽

Viral Infections ◽

Negative Regulator ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Viral Immunity ◽

Type I Ifns ◽

Important Negative Regulator

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140-/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar-/-). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.

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975. Roles of Type I and III Interferon in Severe Pathogenesis of Human Metapneumovirus

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.077 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S34-S35

Author(s):

John V Williams ◽

Yu Zhang ◽

Jiuyang Xu ◽

Margot Miranda-Katz ◽

Helen Rich ◽

...

Keyword(s):

Weight Loss ◽

Disease Severity ◽

Severe Disease ◽

Human Metapneumovirus ◽

Mouse Strains ◽

Type I ◽

Viral Titer ◽

Type I Ifn ◽

Type Iii ◽

Type Iii Ifn

Abstract Background Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood. Methods We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry. Results HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4). Conclusion These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target. Disclosures All Authors: No reported Disclosures.

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Cell-to-Cell Contact as an Efficient Mode of Epstein-Barr Virus Infection of Diverse Human Epithelial Cells

Journal of Virology ◽

10.1128/jvi.72.5.4371-4378.1998 ◽

1998 ◽

Vol 72 (5) ◽

pp. 4371-4378 ◽

Cited By ~ 197

Author(s):

Shosuke Imai ◽

Jun Nishikawa ◽

Kenzo Takada

Keyword(s):

Epithelial Cells ◽

Cell Lines ◽

Viral Gene Expression ◽

Viral Gene ◽

Cell Contact ◽

Barr Virus ◽

Epithelial Cell Lines ◽

Epstein Barr

ABSTRACT We show clear evidence for direct infection of various human epithelial cells by Epstein-Barr virus (EBV) in vitro. The successful infection was achieved by using recombinant EBV (Akata strain) carrying a selective marker gene but without any other artificial operations, such as introduction of the known EBV receptor (CD21) gene or addition of polymeric immunoglobulin A against viral gp350 in culture. Of 21 human epithelial cell lines examined, 18 became infected by EBV, as ascertained by the detection of EBV-determined nuclear antigen (EBNA) 1 expression in the early period after virus exposure, and the following selection culture easily yielded a number of EBV-infected clones from 15 cell lines. None of the human fibroblasts and five nonhuman-derived cell lines examined was susceptible to the infection. By comparison, cocultivation with virus producers showed ≈800-fold-higher efficiency of infection than cell-free infection did, suggesting the significance of direct cell-to-cell contact as a mode of virus spread in vivo. Most of the epithelial cell lines infectable with EBV were negative for CD21 expression at the protein and mRNA levels. The majority of EBV-infected clones established from each cell line invariably expressed EBNA1, EBV-encoded small RNAs, rightward transcripts from theBamHI-A region of the virus genome, and latent membrane protein (LMP) 2A, but not the other EBNAs or LMP1. This restricted form of latent viral gene expression, which is a central issue for understanding epithelial oncogenesis by EBV, resembled that seen in EBV-associated gastric carcinoma and LMP1-negative nasopharyngeal carcinoma. The results indicate that direct infection of epithelial cells by EBV may occur naturally in vivo, and this could be mediated by an unidentified, epithelium-specific binding receptor for EBV. The EBV convertants are viewed, at least in terms of viral gene expression, as in vitro analogs of EBV-associated epithelial tumor cells, thus facilitating analysis of an oncogenic role(s) for EBV in epithelial cells.

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