The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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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Cites
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Collaboration gets the most out of software
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A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures
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Bao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 402
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
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COVID-19 and cellular senescence
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Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model
Tan, B., Zhang, X., Ansari, A., Jadhav, P., Tan, H., Li, K., Chopra, A., Ford, A., Chi, X., Ruiz, F. X., et al. (2024) · Science · doi:10.1126/science.adm9724 · Cited by 131
Self-citationSmall molecules in the treatment of COVID-19
Lei, S., Chen, X., Wu, J., Duan, X., & Men, K. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01249-8 · Cited by 119
“, 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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