tetano
Editor, Senior Moderator
Nature
. 2022 Mar 21.
doi: 10.1038/s41586-022-04630-3. Online ahead of print.
Eicosanoid signaling blockade protects middle-aged mice from severe COVID-19
Lok-Yin Roy Wong[SUP] #[/SUP][SUP] 1 [/SUP], Jian Zheng[SUP] #[/SUP][SUP] 1 [/SUP], Kevin Wilhelmsen[SUP] 2 [/SUP], Kun Li[SUP] 3 [/SUP], Miguel E Ortiz[SUP] 3 [/SUP], Nicholas J Schnicker[SUP] 4 [/SUP], Andrew Thurman[SUP] 5 [/SUP], Alejandro A Pezzulo[SUP] 5 [/SUP], Peter J Szachowicz[SUP] 5 [/SUP], Pengfei Li[SUP] 1 [/SUP], Ruangang Pan[SUP] 1 [/SUP], Klaus Klumpp[SUP] 2 [/SUP], Fred Aswad[SUP] 2 [/SUP], Justin Rebo[SUP] 2 [/SUP], Shuh Narumiya[SUP] 6 [/SUP], Makoto Murakami[SUP] 7 [/SUP], Sonia Zuniga[SUP] 8 [/SUP], Isabel Sola[SUP] 8 [/SUP], Luis Enjuanes[SUP] 8 [/SUP], David K Meyerholz[SUP] 9 [/SUP], Kristen Fortney[SUP] 2 [/SUP], Paul B McCray Jr[SUP] 10 11 [/SUP], Stanley Perlman[SUP] 12 13 [/SUP]
Affiliations
Abstract
Coronavirus disease 2019 (COVID-19) is especially severe in aged populations[SUP]1[/SUP]. SARS-CoV-2 vaccines are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility[SUP]2[/SUP]. 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)[SUP]2[/SUP]. 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 (PGD[SUB]2[/SUB]) and of a phospholipase, PLA[SUB]2[/SUB]G2D, contributed to poor outcomes in aged mice[SUP]3,4[/SUP]. mRNA expression of PLA[SUB]2[/SUB]G2D and PTGDR, a PGD[SUB]2[/SUB] receptor, and production of PGD[SUB]2[/SUB] 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 PLA[SUB]2[/SUB]G2D 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 PLA[SUB]2[/SUB]G2D-PGD[SUB]2[/SUB]/PTGDR pathway is a useful target for therapeutic interventions.
. 2022 Mar 21.
doi: 10.1038/s41586-022-04630-3. Online ahead of print.
Eicosanoid signaling blockade protects middle-aged mice from severe COVID-19
Lok-Yin Roy Wong[SUP] #[/SUP][SUP] 1 [/SUP], Jian Zheng[SUP] #[/SUP][SUP] 1 [/SUP], Kevin Wilhelmsen[SUP] 2 [/SUP], Kun Li[SUP] 3 [/SUP], Miguel E Ortiz[SUP] 3 [/SUP], Nicholas J Schnicker[SUP] 4 [/SUP], Andrew Thurman[SUP] 5 [/SUP], Alejandro A Pezzulo[SUP] 5 [/SUP], Peter J Szachowicz[SUP] 5 [/SUP], Pengfei Li[SUP] 1 [/SUP], Ruangang Pan[SUP] 1 [/SUP], Klaus Klumpp[SUP] 2 [/SUP], Fred Aswad[SUP] 2 [/SUP], Justin Rebo[SUP] 2 [/SUP], Shuh Narumiya[SUP] 6 [/SUP], Makoto Murakami[SUP] 7 [/SUP], Sonia Zuniga[SUP] 8 [/SUP], Isabel Sola[SUP] 8 [/SUP], Luis Enjuanes[SUP] 8 [/SUP], David K Meyerholz[SUP] 9 [/SUP], Kristen Fortney[SUP] 2 [/SUP], Paul B McCray Jr[SUP] 10 11 [/SUP], Stanley Perlman[SUP] 12 13 [/SUP]
Affiliations
- PMID: 35314834
- DOI: 10.1038/s41586-022-04630-3
Abstract
Coronavirus disease 2019 (COVID-19) is especially severe in aged populations[SUP]1[/SUP]. SARS-CoV-2 vaccines are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility[SUP]2[/SUP]. 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)[SUP]2[/SUP]. 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 (PGD[SUB]2[/SUB]) and of a phospholipase, PLA[SUB]2[/SUB]G2D, contributed to poor outcomes in aged mice[SUP]3,4[/SUP]. mRNA expression of PLA[SUB]2[/SUB]G2D and PTGDR, a PGD[SUB]2[/SUB] receptor, and production of PGD[SUB]2[/SUB] 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 PLA[SUB]2[/SUB]G2D 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 PLA[SUB]2[/SUB]G2D-PGD[SUB]2[/SUB]/PTGDR pathway is a useful target for therapeutic interventions.
