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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19
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 . T...
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Published in: | Nature (London) 2022-05, Vol.605 (7908), p.146-151 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
A study reports the isolation and characterization of mouse-adapted SARS-CoV-2, demonstrates asapiprant to protect aged mice from its most severe effects, and identifies the PLA
2
G2D–PGD
2
/PTGDR pathway as a therapeutic target. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-022-04630-3 |