Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

• Published in: Nature (London) 2022-05, Vol.605 (7908), p.146-151
• Main Authors: 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, Rebo, Justin, Narumiya, Shuh, Murakami, Makoto, Zuniga, Sonia, Sola, Isabel, Enjuanes, Luis, Meyerholz, David K., Fortney, Kristen, McCray, Paul B., Perlman, Stanley
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 13/51; 14/63; 45/22; 45/23; 45/44; 45/70; 45/77; 45/90; 631/326/421; 631/326/596/4130; 64/60; 82; 82/51; Adaptation; Aging; Amino acids; Animals; Artificial chromosomes; Cloning; Coronaviruses; COVID-19; Dendritic cells; Dopamine D2 receptors; Eicosanoids; Gene expression; Genomes; Glycoproteins; Humanities and Social Sciences; Infections; Leukocytes, Mononuclear; Lungs; Mice; Middle age; Middle East respiratory syndrome; multidisciplinary; Organic Chemicals; Oxazoles; Peripheral blood mononuclear cells; Phospholipase; Phospholipase A2; Piperazines; Polyesters; Prostaglandin D2; Prostaglandins; Proteins; Respiratory diseases; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Signal transduction; Spike Glycoprotein, Coronavirus; Spike protein; Sulfonamides; Therapeutic applications; Vaccine efficacy; Vaccines; Vectors (Biology); Viral diseases; Virulence; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04630-3

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.