AHR signaling is induced by infection with coronaviruses

AbstractCoronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.

Download Full-text

Influenza A Virus Infection Induces Apical Redistribution of Na+, K+-ATPase in Lung Epithelial Cells In Vitro and In Vivo

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2019-0096le ◽

2019 ◽

Vol 61 (3) ◽

pp. 395-398

Author(s):

Christin Peteranderl ◽

Irina Kuznetsova ◽

Jessica Schulze ◽

Martin Hardt ◽

Emilia Lecuona ◽

...

Keyword(s):

Epithelial Cells ◽

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Influenza A Virus Infection

Download Full-text

Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.740704 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rahwa Taddese ◽

Rian Roelofs ◽

Derk Draper ◽

Xinqun Wu ◽

Shaoguang Wu ◽

...

Keyword(s):

Epithelial Cells ◽

Aryl Hydrocarbon Receptor ◽

Specific Inhibitor ◽

Intestinal Bacteria ◽

Opportunistic Pathogen ◽

Dependent Manner ◽

Aryl Hydrocarbon ◽

Streptococcus Gallolyticus

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

Download Full-text

A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic

10.1101/2020.06.30.180380 ◽

2020 ◽

Cited By ~ 1

Author(s):

Maria Alimova ◽

Eriene-Heidi Sidhom ◽

Abhigyan Satyam ◽

Moran Dvela-Levitt ◽

Michelle Melanson ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Drug Repurposing ◽

Lung Epithelial Cells ◽

Drug Candidate ◽

Mucin 1 ◽

Standing Up

SummaryDrug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.

Download Full-text

DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00031.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. L834-L845 ◽

Cited By ~ 25

Author(s):

Takeshi Kawasaki ◽

Weiguo Chen ◽

Yu Maw Htwe ◽

Koichiro Tatsumi ◽

Steven M. Dudek

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Human Lung ◽

Cell Number ◽

Lung Epithelial Cells ◽

Dpp4 Inhibitors ◽

Anti Inflammatory ◽

Dpp4 Inhibition

Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVECs) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have a therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung ECs in vitro. In vivo, sitagliptin reduced serum DPP4 activity, bronchoalveolar lavage protein concentration, cell number, and proinflammatory cytokine levels after LPS and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVECs isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular ECs (HLMVECs) expressed higher levels of CD26/DPP4 than human pulmonary arterial ECs. LPS induced the release of TNFα, IL-6, and IL-8 by HLMVECs that were inhibited by sitagliptin. LPS promoted the proliferation of HLMVECs, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured ECs or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVECs. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

Download Full-text

Human lung fibroblasts prematurely senescent after exposure to ionizing radiation enhance the growth of malignant lung epithelial cells in vitro and in vivo

International Journal of Oncology ◽

10.3892/ijo.2011.1132 ◽

2011 ◽

Cited By ~ 6

Author(s):

Dimitris Kletsas

Keyword(s):

Epithelial Cells ◽

Ionizing Radiation ◽

Human Lung ◽

Lung Epithelial Cells ◽

Lung Fibroblasts ◽

Human Lung Fibroblasts ◽

Lung Epithelial

Download Full-text

Maresin 1 Maintains the Permeability of Lung Epithelial Cells In Vitro and In Vivo

Inflammation ◽

10.1007/s10753-016-0433-0 ◽

2016 ◽

Vol 39 (6) ◽

pp. 1981-1989 ◽

Cited By ~ 10

Author(s):

Lin Chen ◽

Hong Liu ◽

Yaxin Wang ◽

Haifa Xia ◽

Jie Gong ◽

...

Keyword(s):

Epithelial Cells ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Maresin 1

Download Full-text

Bactofection of lung epithelial cells in vitro and in vivo using a genetically modified Escherichia coli

Gene Therapy ◽

10.1038/sj.gt.3303090 ◽

2008 ◽

Vol 15 (6) ◽

pp. 434-442 ◽

Cited By ~ 11

Author(s):

M D B Larsen ◽

U Griesenbach ◽

S Goussard ◽

D C Gruenert ◽

D M Geddes ◽

...

Keyword(s):

Escherichia Coli ◽

Epithelial Cells ◽

Genetically Modified ◽

Lung Epithelial Cells ◽

Lung Epithelial

Download Full-text

Study Effects of Drug Treatment and Physiological Physical Stimulation on Surfactant Protein Expression of Lung Epithelial Cells Using a Biomimetic Microfluidic Cell Culture Device

Micromachines ◽

10.3390/mi10060400 ◽

2019 ◽

Vol 10 (6) ◽

pp. 400 ◽

Cited By ~ 1

Author(s):

Ting-Ru Lin ◽

Sih-Ling Yeh ◽

Chien-Chung Peng ◽

Wei-Hao Liao ◽

Yi-Chung Tung

Keyword(s):

Cell Culture ◽

Epithelial Cells ◽

Drug Treatment ◽

Surfactant Protein ◽

Lung Epithelial Cells ◽

Single Chip ◽

Physical Stimulation ◽

Lung Epithelial

This paper reports a biomimetic microfluidic device capable of reconstituting physiological physical microenvironments in lungs during fetal development for cell culture. The device integrates controllability of both hydrostatic pressure and cyclic substrate deformation within a single chip to better mimic the in vivo microenvironments. For demonstration, the effects of drug treatment and physical stimulations on surfactant protein C (SPC) expression of lung epithelial cells (A549) are studied using the device. The experimental results confirm the device’s capability of mimicking in vivo microenvironments with multiple physical stimulations for cell culture applications. Furthermore, the results indicate the critical roles of physical stimulations in regulating cellular behaviors. With the demonstrated functionalities and performance, the device is expected to provide a powerful tool for further lung development studies that can be translated to clinical observation in a more straightforward manner. Consequently, the device is promising for construction of more in vitro physiological microenvironments integrating multiple physical stimulations to better study organ development and its functions.

Download Full-text