{"doi":"10.1101/2021.04.20.440676","title":"Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19","abstract":"ABSTRACT Coronavirus disease 2019 (COVID-19) is especially severe in aged populations 1 . Resolution of the COVID-19 pandemic has been advanced by the recent development of SARS-CoV-2 vaccines, but vaccine efficacy is partly compromised by the recent 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 in aged populations. Here, we describe the isolation of a new set of highly virulent mouse-adapted viruses and use them to test a novel therapeutic drug useful in infections of aged animals. Initially, we show that many of the mutations observed in SARS-CoV-2 during mouse adaptation (at positions 417, 484, 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 their selection. Similar to the human infection, aged mice infected with mouse-adapted SARS-CoV-2 develop more severe disease than young mice. In murine SARS, in which severity is also age-dependent, we showed that elevated levels of an eicosanoid, prostaglandin D2 (PGD 2 ) and of a phospholipase, PLA 2 G2D, contributed to poor outcomes in aged mice 3,4 . Using our virulent mouse-adapted SARS-CoV-2, we show that infection of middle-aged mice lacking expression of DP1, a PGD 2 receptor, or PLA 2 G2D are protected from severe disease. Further, treatment with a DP1 antagonist, asapiprant, protected aged mice from a lethal infection. DP1 antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, and demonstrates that the PLA 2 G2D-PGD 2 /DP1 pathway is a useful target for therapeutic interventions. 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Pezzulo","orcid":"0000-0001-7544-5109","position":6,"is_corresponding":false},{"id":805262,"name":"Peter J. Szachowicz","orcid":"0000-0003-1735-297X","position":7,"is_corresponding":false},{"id":805263,"name":"Klaus Klumpp","orcid":"0000-0002-4829-3127","position":8,"is_corresponding":false},{"id":805264,"name":"Fred Aswad","orcid":"0000-0001-9062-3735","position":9,"is_corresponding":false},{"id":805966,"name":"Justin Rebo","orcid":null,"position":10,"is_corresponding":false},{"id":404691,"name":"Shuh Narumiya","orcid":"0000-0001-8062-6529","position":11,"is_corresponding":false},{"id":301714,"name":"Makoto Murakami","orcid":"0000-0002-4565-6017","position":12,"is_corresponding":false},{"id":227015,"name":"David K. Meyerholz","orcid":"0000-0003-1552-3253","position":13,"is_corresponding":false},{"id":805265,"name":"Kristen Fortney","orcid":"0000-0002-6008-2170","position":14,"is_corresponding":false},{"id":225536,"name":"Paul B. 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