Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19

• Published in: The Journal of immunology (1950) 2022-05, Vol.208 (1_Supplement), p.125-125.05
• Main Authors: Zheng, Jian, Wong, Lok-Yin Roy, 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.125.05

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations. 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. 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. 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, elevated levels of an eicosanoid, prostaglandin D2 (PGD2) and of a phospholipase, PLA2G2D, contributed to poor outcomes in aged mice. We now demonstrate that mRNA expression of PLA2G2D and PTGDR, a PGD2 receptor, and production of PGD2 increase in human PBMC-derived dendritic cells with aging and after SARS-CoV-2 infection. Using our virulent 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. This work is supported in part by grants from the National Institutes of Health USA (NIH) (P01 AI060699 (SP, PBM) and RO1 AI129269 (SP) and BIOAGE Labs (SP).  The Pathology Core, is partially supported by the Center for Gene Therapy for Cystic Fibrosis (NIH Grant P30 DK-54759), and the Cystic Fibrosis Foundation. PBM is supported by the Roy J. Carver Charitable Trust.