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 Critical Role of Type III Interferon in Controlling SARS-CoV-2 Infection in Human Intestinal Epithelial Cells

Cell Reports ◽  
2020 ◽  
Vol 32 (1) ◽  
pp. 107863 ◽  
Author(s):  
Megan L. Stanifer ◽  
Carmon Kee ◽  
Mirko Cortese ◽  
Camila Metz Zumaran ◽  
Sergio Triana ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Critical Role ◽  
Intestinal Epithelial ◽  
Type Iii ◽  
Human Intestinal Epithelial Cells ◽  
Type Iii Interferon

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 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 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 Gellan Gum Promotes the Differentiation of Enterocytes from Human Induced Pluripotent Stem Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 951
Author(s):  
Shimeng Qiu ◽  
Tomoki Kabeya ◽  
Isamu Ogawa ◽  
Shiho Anno ◽  
Hisato Hayashi ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cells ◽  
Drug Absorption ◽  
Intestinal Epithelial Cells ◽  
Critical Role ◽  
Gellan Gum ◽  
Peptide Transporter ◽  
Control Group ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells

The evaluation of drug pharmacokinetics in the small intestine is critical for developing orally administered drugs. Caucasian colon adenocarcinoma (Caco-2) cells are employed to evaluate drug absorption in preclinical trials of drug development. However, the pharmacokinetic characteristics of Caco-2 cells are different from those of the normal human small intestine. Besides this, it is almost impossible to obtain primary human intestinal epithelial cells of the same batch. Therefore, human iPS cell-derived enterocytes (hiPSEs) with pharmacokinetic functions similar to human intestinal epithelial cells are expected to be useful for the evaluation of drug absorption. Previous studies have been limited to the use of cytokines and small molecules to generate hiPSEs. Dietary fibers play a critical role in maintaining intestinal physiology. We used gellan gum (GG), a soluble dietary fiber, to optimize hiPSE differentiation. hiPSEs cocultured with GG had significantly higher expression of small intestine- and pharmacokinetics-related genes and proteins. The activities of drug-metabolizing enzymes, such as cytochrome P450 2C19, and peptide transporter 1 were significantly increased in the GG treatment group compared to the control group. At the end point of differentiation, the percentage of senescent cells increased. Therefore, GG could improve the differentiation efficiency of human iPS cells to enterocytes and increase intestinal maturation by extending the life span of hiPSEs.

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.

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