Hypoxia Inducible Factors Regulate Infectious SARS-CoV-2, Epithelial Damage and Respiratory Symptoms in a Hamster COVID-19 Model

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2022 Sep 6

PMID 36067210

Authors

Peter A C Wing

Maria Prange-Barczynska

Amy Cross

Stefania Crotta

Claudia Orbegozo Rubio

Xiaotong Cheng

James M Harris

Xiaodong Zhuang

Rachel L Johnson

Kathryn A Ryan

Yper Hall

Miles W Carroll

Fadi Issa

Peter Balfe

Andreas Wack

Tammie Bishop

Francisco J Salguero

Jane A McKeating

Affiliations

Soon will be listed here.

Abstract

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

Citing Articles

Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein.

Wei X, Zhou Y, Shen X, Fan L, Liu D, Gao X Acta Pharm Sin B. 2024; 14(6):2505-2519.

PMID: 38828154 PMC: 11143514. DOI: 10.1016/j.apsb.2024.03.009.

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome.

Chernov A, Rodionov M, Kazakov V, Ivanova K, Meshcheryakov F, Kudriaeva A Front Pharmacol. 2024; 15:1351655.

PMID: 38449806 PMC: 10915062. DOI: 10.3389/fphar.2024.1351655.

The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation.

Farahani E, Reinert L, Narita R, Serrero M, Skouboe M, van der Horst D Cell Rep. 2024; 43(2):113792.

PMID: 38363679 PMC: 10915869. DOI: 10.1016/j.celrep.2024.113792.

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression.

Zhuang X, Gallo G, Sharma P, Ha J, Magri A, Borrmann H iScience. 2024; 27(1):108763.

PMID: 38261926 PMC: 10797196. DOI: 10.1016/j.isci.2023.108763.

The N6-methyladenosine demethylase ALKBH5 regulates the hypoxic HBV transcriptome.

Tsukuda S, Harris J, Magri A, Balfe P, Siddiqui A, Wing P PLoS Pathog. 2024; 20(1):e1011917.

PMID: 38227578 PMC: 10817175. DOI: 10.1371/journal.ppat.1011917.

References

van Dam T, Kennedy J, van der Lee R, de Vrieze E, Wunderlich K, Rix S . CiliaCarta: An integrated and validated compendium of ciliary genes. PLoS One. 2019; 14(5):e0216705. PMC: 6522010. DOI: 10.1371/journal.pone.0216705. View

Cross A, de Andrea C, Villalba-Esparza M, Landecho M, Cerundolo L, Weeratunga P . Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury. JCI Insight. 2022; 8(2). PMC: 9977306. DOI: 10.1172/jci.insight.157837. View

Haeberle H, Durrstein C, Rosenberger P, Hosakote Y, Kuhlicke J, Kempf V . Oxygen-independent stabilization of hypoxia inducible factor (HIF)-1 during RSV infection. PLoS One. 2008; 3(10):e3352. PMC: 2556398. DOI: 10.1371/journal.pone.0003352. View

Khoury J, Ibla J, Neish A, Colgan S . Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation. J Clin Invest. 2007; 117(3):703-11. PMC: 1797604. DOI: 10.1172/JCI30049. View

Owen D, Allerton C, Anderson A, Aschenbrenner L, Avery M, Berritt S . An oral SARS-CoV-2 M inhibitor clinical candidate for the treatment of COVID-19. Science. 2021; 374(6575):1586-1593. DOI: 10.1126/science.abl4784. View

Schodel J, Oikonomopoulos S, Ragoussis J, Pugh C, Ratcliffe P, Mole D . High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011; 117(23):e207-17. PMC: 3374576. DOI: 10.1182/blood-2010-10-314427. View

Ren L, Zhang W, Han P, Zhang J, Zhu Y, Meng X . Influenza A virus (H1N1) triggers a hypoxic response by stabilizing hypoxia-inducible factor-1α via inhibition of proteasome. Virology. 2019; 530:51-58. DOI: 10.1016/j.virol.2019.02.010. View

Caly L, Druce J, Roberts J, Bond K, Tran T, Kostecki R . Isolation and rapid sharing of the 2019 novel coronavirus (SARS-CoV-2) from the first patient diagnosed with COVID-19 in Australia. Med J Aust. 2020; 212(10):459-462. PMC: 7228321. DOI: 10.5694/mja2.50569. View

Palazon A, Goldrath A, Nizet V, Johnson R . HIF transcription factors, inflammation, and immunity. Immunity. 2014; 41(4):518-28. PMC: 4346319. DOI: 10.1016/j.immuni.2014.09.008. View

10.

Wing P, Keeley T, Zhuang X, Lee J, Prange-Barczynska M, Tsukuda S . Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells. Cell Rep. 2021; 35(3):109020. PMC: 8020087. DOI: 10.1016/j.celrep.2021.109020. View

11.

Akizawa T, Otsuka T, Reusch M, Ueno M . Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open-Label Study. Ther Apher Dial. 2019; 24(2):115-125. PMC: 7079122. DOI: 10.1111/1744-9987.12888. View

12.

Hiscox J, Khoo S, Stewart J, Owen A . Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance?. J Antimicrob Chemother. 2021; 76(9):2230-2233. PMC: 8361339. DOI: 10.1093/jac/dkab189. View

13.

Liu P, Balfe P, McKeating J, Schilling M . Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis. Viruses. 2020; 12(11). PMC: 7693908. DOI: 10.3390/v12111213. View

14.

Manohar P, Loh B, Nachimuthu R, Hua X, Welburn S, Leptihn S . Secondary Bacterial Infections in Patients With Viral Pneumonia. Front Med (Lausanne). 2020; 7:420. PMC: 7419580. DOI: 10.3389/fmed.2020.00420. View

15.

Alanio A, Delliere S, Fodil S, Bretagne S, Megarbane B . Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 2020; 8(6):e48-e49. PMC: 7239617. DOI: 10.1016/S2213-2600(20)30237-X. View

16.

Morris D, Qu Y, Agrawal A, Garofalo R, Casola A . HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus. Viruses. 2020; 12(10). PMC: 7601280. DOI: 10.3390/v12101088. View

17.

Huo J, Mikolajek H, Le Bas A, Clark J, Sharma P, Kipar A . A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat Commun. 2021; 12(1):5469. PMC: 8458290. DOI: 10.1038/s41467-021-25480-z. View

18.

Voysey M, Clemens S, Madhi S, Weckx L, Folegatti P, Aley P . Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2020; 397(10269):99-111. PMC: 7723445. DOI: 10.1016/S0140-6736(20)32661-1. View

19.

Nouailles G, Wyler E, Pennitz P, Postmus D, Vladimirova D, Kazmierski J . Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19. Nat Commun. 2021; 12(1):4869. PMC: 8357947. DOI: 10.1038/s41467-021-25030-7. View

20.

Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T . Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial. Clin J Am Soc Nephrol. 2020; 15(8):1155-1165. PMC: 7409739. DOI: 10.2215/CJN.16011219. View