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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19
Open accessAbstract
Coronavirus disease 2019 (COVID-19) is especially severe in aged populations 1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility 2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern 2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D 2 (PGD 2)) and a phospholipase (phospholipase A2 group 2D (PLA 2 G2D)) contributed to poor outcomes in aged mice 3,4. mRNA expression of PLA 2 G2D and prostaglandin D 2 receptor (PTGDR), and production of PGD 2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA 2 G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA 2 G2D-PGD 2/PTGDR pathway is a useful target for therapeutic interventions.
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“The levels of PGD2 and related prostaglandins were also found to be increased in older individuals and in individuals infected with SARS-CoV-2 (ref.134).”
From COVID-19 and cellular senescence (2023) · cites this paper as [134]
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Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2015432 · Cited by 5,613
Wan, Y., Shang, J., Graham, R., Baric, R. S., & Li, F. (2020) · Journal of Virology · doi:10.1128/jvi.00127-20 · Cited by 4,341
Starr, T. N., Greaney, A. J., Hilton, S. K., Ellis, D., Crawford, K. H. D., Dingens, A. S., Navarro, M. J., Bowen, J. E., Tortorici, M. A., Walls, A. C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.012 · Cited by 1,956
Severe acute respiratory syndrome
Peiris, M. J. S., Guan, Y., & Yuen, K. (2004) · Nature Medicine · doi:10.1038/nm1143 · Cited by 1,157
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice
Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2312-y · Cited by 1,126
Collaboration gets the most out of software
Morin, A., Eisenbraun, B., Key, J., Sanschagrin, P. C., Timony, M. A., Ottaviano, M., & Piotr Sliz, A. (2013) · eLife · doi:10.7554/elife.01456 · Cited by 1,055
Winkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., Fox, J. M., Chen, R. E., Earnest, J. T., Keeler, S. P., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0778-2 · Cited by 901
Viral and host factors related to the clinical outcome of COVID-19
Zhang, X., Tan, Y., Ling, Y., Lü, G., Liu, F., Yi, Z., Jia, X., Wu, M., Shi, B., Xu, S., et al. (2020) · Nature · doi:10.1038/s41586-020-2355-0 · Cited by 874
Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy
Gu, H., Chen, Q., Yang, G., He, L., Fan, H., Deng, Y.-Q., Wang, Y., Teng, Y., Zhao, Z., Cui, Y., et al. (2020) · Science · doi:10.1126/science.abc4730 · Cited by 762
A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures
Dinnon, K. H., Leist, S. R., Schäfer, A., Edwards, C. E., Martinez, D. R., Montgomery, S. A., West, A., Yount, B. L., Hou, Y. J., Adams, L. E., et al. (2020) · Nature · doi:10.1038/s41586-020-2708-8 · Cited by 675
A Mouse Model of SARS-CoV-2 Infection and Pathogenesis
Sun, S.-H., Chen, Q., Gu, H.-J., Yang, G., Wang, Y.-X., Huang, X.-Y., Liu, S.-S., Zhang, N.-N., Li, X.-F., Xiong, R., et al. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.05.020 · Cited by 617
A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice
Leist, S. R., Dinnon, K. H., Schäfer, A., Tse, L. V., Okuda, K., Hou, Y. J., West, A., Edwards, C. E., Sanders, W., Fritch, E. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.050 · Cited by 613
The Genotype-Tissue Expression (GTEx) Project
Carithers, L. J., & Moore, H. M. (2015) · Biopreservation and Biobanking · doi:10.1089/bio.2015.29031.hmm · Cited by 549
Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2
Jiang, R.-D., Liu, M.-Q., Chen, Y., Shan, C., Zhou, Y.-W., Shen, X.-R., Li, Q., Zhang, L., Zhu, Y., Si, H.-R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.027 · Cited by 548
Galani, I.-E., Rovina, N., Lampropoulou, V., Triantafyllia, V., Manioudaki, M., Pavlos, E., Koukaki, E., Fragkou, P. C., Panou, V., Rapti, V., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00840-x · Cited by 503
COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice
Zheng, J. H., Wong, L.-Y. R., Li, K., Verma, A. K., Ortiz, M. E., Wohlford-Lenane, C., Leidinger, M., Knudson, C. M., Meyerholz, D. K., McCray, P. B., et al. (2020) · Nature · doi:10.1038/s41586-020-2943-z · Cited by 500
Self-citationA SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies
Hassan, A. O., Case, J. B., Winkler, E. S., Thackray, L. B., Kafai, N. M., Bailey, A. L., McCune, B. T., Fox, J. M., Chen, R. E., Alsoussi, W. B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.011 · Cited by 482
Self-citationLi, K., Wohlford-Lenane, C., Perlman, S., Zhao, J., Jewell, A. K., Reznikov, L. R., Gibson-Corley, K. N., Meyerholz, D. K., & McCray, P. B. (2016) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv499 · Cited by 459
Self-citationA Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice
Roberts, A., Deming, D., Paddock, C. D., Cheng, A., Yount, B. L., Vogel, L., Herman, B. D., Sheahan, T., Heise, M. T., Genrich, G. L., et al. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030005 · Cited by 447
Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment
Sun, J., Zhuang, Z., Zheng, J. H., Li, K., Wong, R. L.-Y., Liu, D., Huang, J., He, J., Zhu, A., Zhao, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.010 · Cited by 440
Self-citationPrinciples and approaches for reproducible scoring of tissue stains in research
Meyerholz, D. K., & Beck, A. P. (2018) · Laboratory Investigation · doi:10.1038/s41374-018-0057-0 · Cited by 350
Self-citationSARS-CoV-2 501Y.V2 variants lack higher infectivity but do have immune escape
Li, Q., Nie, J., Wu, J., Zhang, L., Ding, R., Wang, H., Zhang, Y., Li, T., Liu, S., Zhang, M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.042 · Cited by 346
The variant gambit: COVID-19’s next move
Plante, J. A., Mitchell, B. M., Plante, K. S., Debbink, K., Weaver, S. C., & Menachery, V. D. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.02.020 · Cited by 328
Abani, O., Abbas, A., Abbas, F., Abbas, M. A., Abbasi, S., Abbass, H., Abbott, A., Abdallah, N., Abdelaziz, A., Abdelfattah, M., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)01825-0 · Cited by 302
Almazán, F., DeDiego, M. L., Sola, I., Zúñiga, S., Nieto-Torres, J. L., Márquez-Jurado, S., Andrés, G., & Enjuanes, L. (2013) · mBio · doi:10.1128/mbio.00650-13 · Cited by 277
Self-citationZhao, J., Zhao, J., Legge, K., & Perlman, S. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59777 · Cited by 265
Self-citationRECOVERY Collaborative Group, Horby, P. W., Campbell, M., Spata, E., Emberson, J., Staplin, N., Pessoa-Amorim, G., Peto, L., Wiselka, M., Wiffen, L., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00435-5 · Cited by 229
Yoshikawa, T., Hill, T. E., Yoshikawa, N., Popov, V. L., Galindo, C. L., Garner, H. R., Peters, C. J., & Tseng, C.-T. K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008729 · Cited by 187
Zheng, J. H., Wang, Y., Li, K., Meyerholz, D. K., Allamargot, C., & Perlman, S. M. (2020) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiaa753 · Cited by 165
Self-citationVijay, R., Hua, X., Meyerholz, D. K., Miki, Y., Yamamoto, K., Gelb, M. H., Murakami, M., & Perlman, S. M. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150632 · Cited by 143
Self-citationMiki, Y., Yamamoto, K., Taketomi, Y., Sato, H., Shimo, K., Kobayashi, T., Ishikawa, Y., Ishii, T., Nakanishi, H., Ikeda, K., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121887 · Cited by 139
Self-citationFurusawa, H., Cardwell, J., Okamoto, T., Walts, A. D., Konigsberg, I. R., Kurche, J. S., Bang, T. J., Schwarz, M. I., Brown, K. K., Kropski, J. A., et al. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202001-0134oc · Cited by 137
Highly Specific and Broadly Potent Inhibitors of Mammalian Secreted Phospholipases A2
Oslund, R., Cermak, N., & Gelb, M. H. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800422v · Cited by 136
Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice
Huang, K., Zhang, Y., Hui, X., Zhao, Y., Gong, W., Wang, T., Zhang, S., Yang, Y., Deng, F., Zhang, Q., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103381 · Cited by 119
Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2
Sun, S., Gu, H., Cao, L., Chen, Q., Ye, Q., Yang, G., Li, R.-T., Fan, H., Deng, Y.-Q., Song, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25903-x · Cited by 104
Channappanavar, R., & Perlman, S. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci144115 · Cited by 94
Self-citationWang, J., Shuai, L., Wang, C., Liu, R., He, X., Zhang, X., Sun, Z., Shan, D., Ge, J., Wang, X., et al. (2020) · Protein & Cell · doi:10.1007/s13238-020-00767-x · Cited by 89
Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer
Miki, Y., Kidoguchi, Y., Sato, M., Taketomi, Y., Taya, C., Muramatsu, K., Gelb, M. H., Yamamoto, K., & Murakami, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.734624 · Cited by 80
Self-citationDrake, T. M., Fairfield, C. J., Pius, R., Knight, S. R., Norman, L., Girvan, M., Hardwick, H. E., Docherty, A. B., Thwaites, R. S., Openshaw, P., et al. (2021) · The Lancet Rheumatology · doi:10.1016/s2665-9913(21)00104-1 · Cited by 73
Antiplatelet therapy and outcome in COVID-19: the Health Outcome Predictive Evaluation Registry
Santoro, F., Nuñez-Gil, I. J., Vitale, E., Viana-Llamas, M. C., Reche-Martínez, B., Romero-Pareja, R., Guzmán, G. I. F., Rozas, I. F., Uribarri, A., Becerra‐Muñoz, V. M., et al. (2021) · Heart · doi:10.1136/heartjnl-2021-319552 · Cited by 64
Marone, G., Galdiero, M. R., Pecoraro, A., Pucino, V., Criscuolo, G., Triassi, M., & Varricchi, G. (2019) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1555237 · Cited by 62
SARS-CoV-2 Rapidly Adapts in Aged BALB/c Mice and Induces Typical Pneumonia
Zhang, Y., Huang, K. L., Wang, T., Dèng, F., Gong, W., Hui, X., Zhao, Y., He, X., Li, C., Zhang, Q., et al. (2021) · Journal of Virology · doi:10.1128/jvi.02477-20 · Cited by 44
Non-steroidal anti-inflammatory drug use in COVID-19
Kragholm, K. H., Torp-Pedersen, C. T., & Fosbøl, E. L. (2021) · The Lancet Rheumatology · doi:10.1016/s2665-9913(21)00144-2 · Cited by 32
Fehr, A. R. (2019) · Methods in molecular biology · doi:10.1007/978-1-0716-0211-9_5 · Cited by 29
Takahashi, G., Asanuma, F., Suzuki, N., Hattori, M., Sakamoto, S. X., Kugimiya, A., Tomita, Y., Kuwajima, G., Abraham, W. M., Deguchi, M., et al. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.08.003 · Cited by 22
Hirano, Y., Shichijo, M., Deguchi, M., Nagira, M., Suzuki, N., Nishitani, Y., Hattori, M., & Arimura, A. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.01.003 · Cited by 20
Ullah, M. A., Rittchen, S., Li, J., Hasnain, S. Z., & Phipps, S. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00405-7 · Cited by 16
Hirano, Y., Shichijo, M., Ikeda, M., Kitaura, M., Tsuchida, J., Asanuma, F., Yanagimoto, T., Furue, Y., Imura, K., Yasui, K., et al. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.05.003 · Cited by 11
Does aspirin save lives in patients with COVID-19?
Voruganti, D. C., Bassareo, P. P., Calcaterra, G., & Mehta, J. L. (2021) · Heart · doi:10.1136/heartjnl-2021-320255 · Cited by 9
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Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 172
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“, treatment with asapiprant could protect aged mice from lethal SARS-CoV-2 infection, since elevated levels of prostaglandin D2 (PGD2) contribute to poor outcomes in SARSCoV-2-infected aged mice.(492) Proxalutamide is an androgen receptor antagonist, which also contains an oxazole ring, and it exhibited anti-SARS-CoV-…”
Background
Metadata
- Authors
- Wong, L.-Y. R., Zheng, J., Wilhelmsen, K., Li, K., Ortiz, M. E., Schnicker, N. J., Thurman, A., Pezzulo, A. A., Szachowicz, P. J., Li, P., Pan, R., Klumpp, K., Aswad, F., Rebo, J., Narumiya, S., Murakami, M., Zuniga, S., Sola, I., Enjuanes, L., Meyerholz, D. K., Fortney, K., McCray, P. B., & Perlman, S.
- Affiliations
- University of Iowa (US)
- Kyoto University (JP)
- Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- McCray, Paul B.
- Perlman, Stanley
- ORCID
- Wong, Lok-Yin Roy
- Zheng, Jian
- Wilhelmsen, Kevin
- Li, Kun
- Ortiz, Miguel E.
- Schnicker, Nicholas J.
- Thurman, Andrew
- Pezzulo, Alejandro A.
- Szachowicz, Peter J.
- Li, Pengfei
- Pan, Ruangang
- Klumpp, Klaus
- Aswad, Fred
- Narumiya, Shuh
- Murakami, Makoto
- Zuniga, Sonia
- Sola, Isabel
- Enjuanes, Luis
- Meyerholz, David K.
- Fortney, Kristen
- McCray, Paul B.
- Perlman, Stanley
- Venue
- Nature
- Published
- 2022-03-21
- Volume
- 605
- Issue
- 7908
- Pages
- 146-151
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9783543
- OpenAlex
- W4221027163
- Semantic Scholar
- 1b2a5f58f143f03b3e8a769283ac4c513f4b72f8
- Cited by
- 178
- References
- 49
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 59 · 2023: 43 · 2022: 21
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Cystic Fibrosis Foundation
- Roy J. Carver Charitable Trust
- University of Washington
- National Institutes of Health (P30 DK, T32 AI007511, AI060699, P30 DK-54759, AI007511)
- National Heart, Lung, and Blood Institute (K01HL140261, R01HL163024)
- National Institute of Allergy and Infectious Diseases (T32 AI007511, P01AI060699, R01AI129269)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK054759)
- National Institute of Environmental Health Sciences (P30ES005605)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Keywords
- COVID-19 pandemic, SARS-CoV-2, prostaglandin D2, prostaglandin D2 receptor, aging, aged mice, SARS-CoV-2 variants, spike protein mutations, dendritic cells, disease severity
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Leukocytes, Mononuclear, Organic Chemicals, Oxazoles, Piperazines, Polyesters, Prostaglandins, Sulfonamides, Eicosanoids, Mice, Spike Glycoprotein, Coronavirus
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