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 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 LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway

2012 ◽  
Vol 302 (6) ◽  
pp. G618-G627 ◽  
Author(s):  
Amika Singla ◽  
Anoop Kumar ◽  
Shubha Priyamvada ◽  
Maliha Tahniyath ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Gene Transcription ◽  
Promoter Activity ◽  
Intestinal Epithelial Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Short Term ◽  
Exchange Activity

DRA (downregulated in adenoma) or SLC26A3 is the major apical anion exchanger mediating Cl− absorption in intestinal epithelial cells. Disturbances in DRA function and expression have been implicated in diarrheal conditions such as congenital chloride diarrhea and inflammatory bowel diseases. Previous studies have shown that DRA is subject to regulation by short-term and transcriptional mechanisms. In this regard, we have recently shown that short-term treatment by lysophosphatidic acid (LPA), an important bioactive phospholipid, stimulates Cl−/HCO3−(OH−) exchange activity via an increase in DRA surface levels in human intestinal epithelial cells. However, the long-term effects of LPA on DRA at the level of gene transcription have not been examined. The present studies were aimed at investigating the effects of LPA on DRA function and expression as well as elucidating the mechanisms underlying its transcriptional regulation. Long-term LPA treatment increased the Cl−/HCO3− exchange activity in Caco-2 cells. LPA treatment (50–100 μM) of Caco-2 cells significantly stimulated DRA mRNA levels and DRA promoter activity (−1183/+114). This increase in DRA promoter activity involved the LPA2 receptor and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. Progressive deletions from −1183/+114 to −790/+114 abrogated the stimulatory effects of LPA, indicating that the −1183/−790 promoter region harbors LPA response elements. Utilizing EMSA and mutational studies, our results showed that LPA induced the DRA promoter activity in a c-Fos-dependent manner. LPA also increased the protein expression of c-Fos and c-Jun in Caco-2 cells. Furthermore, overexpression of c-Fos but not c-Jun enhanced the DRA promoter activity. This increase in DRA transcription in response to LPA indicates that LPA may act as an antidiarrheal agent and could be exploited for the treatment of diarrhea associated with inflammatory or infectious diseases of the gut.

scholarly journals In Vivo-Induced InvA-Like Autotransporters Ifp and InvC of Yersinia pseudotuberculosis Promote Interactions with Intestinal Epithelial Cells and Contribute to Virulence

2011 ◽  
Vol 80 (3) ◽  
pp. 1050-1064 ◽  
Author(s):  
Fabio Pisano ◽  
Annika Kochut ◽  
Frank Uliczka ◽  
Rebecca Geyer ◽  
Tatjana Stolz ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Yersinia Pseudotuberculosis ◽  
Intestinal Epithelial Cells ◽  
Bacterial Colonization ◽  
Immune Defense ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Intestinal Epithelial ◽  
Content Type ◽  
K 12

TheYersinia pseudotuberculosisIfp and InvC molecules are putative autotransporter proteins with a high homology to the invasin (InvA) protein. To characterize the function of these surface proteins, we expressed both factors inEscherichia coliK-12 and demonstrated the attachment of Ifp- and InvC-expressing bacteria to human-, mouse-, and pig-derived intestinal epithelial cells. Ifp also was found to mediate microcolony formation and internalization into polarized human enterocytes. TheifpandinvCgenes were not expressed underin vitroconditions but were found to be induced in the Peyer's patches of the mouse intestinal tract. In a murine coinfection model, the colonization of the Peyer's patches and the mesenteric lymph nodes of mice by theifp-deficient strain was significantly reduced, and considerably fewer bacteria reached liver and spleen. The absence of InvC did not have a severe influence on bacterial colonization in the murine infection model, and it resulted in only a slightly reduced number ofinvCmutants in the Peyer's patches. The analysis of the host immune response demonstrated that the presence of Ifp and InvC reduced the recruitment of professional phagocytes, especially neutrophils, in the Peyer's patches. These findings support a role for the adhesins in modulating host-pathogen interactions that are important for immune defense.

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 Genetic Mechanisms Underlying the Pathogenicity of Cold-Stressed Salmonella enterica Serovar Typhimurium in Cultured Intestinal Epithelial Cells

2014 ◽  
Vol 80 (22) ◽  
pp. 6943-6953 ◽  
Author(s):  
Jigna Shah ◽  
Prerak T. Desai ◽  
Bart C. Weimer
Keyword(s):  
Epithelial Cells ◽  
Host Cell ◽  
Intestinal Epithelial Cells ◽  
Acid Stress ◽  
Intestinal Epithelial ◽  
Cell Infection ◽  
Antioxidant Genes ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Adhesion And Invasion

ABSTRACTSalmonellaencounters various stresses in the environment and in the host during infection. The effects of cold (5°C, 48 h), peroxide (5 mM H2O2, 5 h) and acid stress (pH 4.0, 90 min) were tested on pathogenicity ofSalmonella. Prior exposure ofSalmonellato cold stress significantly (P< 0.05) increased adhesion and invasion of cultured intestinal epithelial (Caco-2) cells. This increasedSalmonella-host cell association was also correlated with significant induction of several virulence-associated genes, implying an increased potential of cold-stressedSalmonellato cause an infection. In Caco-2 cells infected with cold-stressedSalmonella, genes involved in the electron transfer chain were significantly induced, but no simultaneous significant increase in expression of antioxidant genes that neutralize the effect of superoxide radicals or reactive oxygen species was observed. Increased production of caspase 9 and caspase 3/7 was confirmed during host cell infection with cold-stressedSalmonella. Further, a prophage gene,STM2699, induced in cold-stressedSalmonellaand a spectrin gene, SPTAN1, induced inSalmonella-infected intestinal epithelial cells were found to have a significant contribution in increased adhesion and invasion of cold-stressedSalmonellain epithelial cells.

Lactase Gene Transcription Is Activated in Response to Hypoxia in Intestinal Epithelial Cells

2002 ◽  
Vol 75 (1) ◽  
pp. 65-69 ◽  
Author(s):  
So Young Lee ◽  
Ashima Madan ◽  
Glenn T. Furuta ◽  
Sean P. Colgan ◽  
Eric Sibley
Keyword(s):  
Epithelial Cells ◽  
Gene Transcription ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Lactase Gene
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