Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1. SARS-CoV-2 vaccines are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially in aged populations. Here, we describe the isolation of highly virulent mouse-adapted viruses and use them to test a novel therapeutic drug in infected aged animals. Many of the mutations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498, 501 of the spike protein) also arise in humans in variants of concern (VOC)2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. In murine SARS, in which severity is also age-dependent, elevated levels of an eicosanoid, prostaglandin D2 (PGD2) and of a phospholipase, PLA2G2D, contributed to poor outcomes in aged mice3,4. mRNA expression of PLA2G2D and PTGDR, a PGD2 receptor, and production of PGD2 also increase in human PBMC-derived dendritic cells with aging and after SARS-CoV-2 infection. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR, or PLA2G2D are protected from severe disease. Further, 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 PLA2G2D-PGD2/PTGDR pathway is a useful target for therapeutic interventions.



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