Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus

Mihaylova, Valia T.; Kong, Yong; Fedorova, Olga; Sharma, Lokesh; Cruz, Charles S. Dela; Pyle, Anna Marie; Iwasaki, Akiko; Foxman, Ellen F.

doi:10.1016/j.celrep.2018.08.033

Cited by 50 publications

(46 citation statements)

References 42 publications

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“…The ability of NRF2 inducers to also reduce potentially pathogenic IFN-and inflammatory responses while retaining their antiviral properties is unique to these compounds and highlights their potential to control virus-induced pathology. That NRF2 might be a natural regulator of IFN-responses in the airway epithelium is supported by a recent report demonstrating that NRF2 activity is high while IFN activity is low in the bronchial epithelium 29 . Our discovery that NRF2 seems to affect stability of IRF3 dimerization adds to the notion that NRF2 is a more universal regulator of type I IFN induction, while keeping in mind that this is not the only mechanism through which this could be achieved.…”

Section: Discussionmentioning

confidence: 83%

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

et al. 2020

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Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.

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Section: Discussionmentioning

confidence: 83%

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

et al. 2020

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“…The ability of these NRF2 inducers to also reduce potentially pathogenic IFN-and inflammatory responses while retaining their anti-viral properties is unique to these compounds and promotes their applicability to prevent virus-induced pathology. That NRF2 might be a natural regulator of IFN-responses in the airway epithelium is supported by a recent report demonstrating that NRF2 activity is high while IFN activity is low in the bronchial epithelium (29). As DMF is currently used as an anti-inflammatory drug in relapsing-remitting MS, this drug could be easily repurposed and tested in clinical trials to test its ability to limit SARS-CoV2 replication and inflammationinduced pathology in COVID-19 patients.…”

Section: Discussionmentioning

confidence: 92%

Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Olagnier

Farahani

Thyrsted

et al. 2020

Preprint

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Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.

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“…Human nasal epithelial cells (HNECs) were purchased (PromoCell; Heidelberg, Germany), and cultured (37 °C, 5% CO 2 , fully humidified) in airway epithelial cell growth medium. Subcultures were established, according to manufacturer's instructions [16]. The cells were incubated (45 min, 39.5 °C) and harvested 1 h after heat shock for our purposes.…”

Section: Cell Culturementioning

confidence: 99%

Differential Nasal Expression of Heat Shock Proteins 27 and 70 by Aerobic Exercise: A Preliminary Study

Min

Kang

et al. 2020

Int. J. Med. Sci.

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Purpose: Exercise modifies airway immune responses and susceptibility to infection. We investigated the effects of exercise on two HSPs (heat shock proteins), quantifying expression levels in nasal mucosa of both professional competitive athletes and non-athletes for comparison. Method: We used western blot technique to determine expression levels of HSPs in primary human nasal epithelial cells (HNECs). Nasal lavage (NAL) fluids were collected from 12 male professional volley ball players and 6 healthy males pre-submaximal exercise (running for 30 min at 70-80% of maximal heart rate) and post-submaximal exercise. Expression levels of HSP27, HSP70, Interleukin (IL)-8, and Tumor necrosis factor (TNF)-α in NAL fluids were quantified by enzyme-linked immunosorbent assay (ELISA), and difference of the level between pre-submaximal exercise and post-submaximal exercise was statistically analyzed. Antibacterial assay using Staphylococcus aureus was performed to assess the immunological role of HSPs in NAL fluids. Results:. In non-athlete controls, HSP27, HSP70, and IL-8 were unchanged after exercise. In the professional athletes, HSP70 expression was declined significantly (p<0.05), but HSP27 was not significantly changed. IL-8 and TNF-α did not show significant difference, either. By antibacterial assay, it was found that the number of active bacterial populations were influenced by the presence or absence of HSP27 and HSP70 in NAL fluids. Conclusion: HSP27 and HSP70 were present in NAL fluids of enrolled subjects, and the effect of exercise on the level HSPs was different between professional athletic competitors and non-athletes. As the number of active bacterial population was influenced by the presence or absence of nasal HSP27 and HSP70, we suggest that HSP27 and HSP70 may play immunological function in NAL fluids.

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Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus

Cited by 50 publications

References 42 publications

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Differential Nasal Expression of Heat Shock Proteins 27 and 70 by Aerobic Exercise: A Preliminary Study

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