Jian Zheng
Profile Url: jian-zheng
Postdoctoral Research Scholar at University of Iowa, Department of Microbiology
<p class="body-1"></p><p><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">Coronavirus disease 2019 (COVID-19) is especially severe in aged populations</span><a href="https://www.biorxiv.org/content/10.1101/2021.04.20.440676v1#ref-1" style="background-color: rgb(255, 255, 255); font-family: Roboto, sans-serif; font-weight: 400;"><span style="font-weight: 700;">1</span></a><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">. 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</span><a href="https://www.biorxiv.org/content/10.1101/2021.04.20.440676v1#ref-2" style="background-color: rgb(255, 255, 255); font-family: Roboto, sans-serif; font-weight: 400;"><span style="font-weight: 700;">2</span></a><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">. 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)</span><a href="https://www.biorxiv.org/content/10.1101/2021.04.20.440676v1#ref-2" style="background-color: rgb(255, 255, 255); font-family: Roboto, sans-serif; font-weight: 400;"><span style="font-weight: 700;">2</span></a><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">. 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 (PGD2) and of a phospholipase, PLA2G2D, contributed to poor outcomes in aged mice</span><a href="https://www.biorxiv.org/content/10.1101/2021.04.20.440676v1#ref-3" style="background-color: rgb(255, 255, 255); font-family: Roboto, sans-serif; font-weight: 400;"><span style="font-weight: 700;">3</span></a><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">,</span><a href="https://www.biorxiv.org/content/10.1101/2021.04.20.440676v1#ref-4" style="background-color: rgb(255, 255, 255); font-family: Roboto, sans-serif; font-weight: 400;"><span style="font-weight: 700;">4</span></a><span style="color: rgba(0, 0, 0, 0.75); background-color: rgb(255, 255, 255);">. Using our virulent mouse-adapted SARS-CoV-2, we show that infection of middle-aged mice lacking expression of DP1, a PGD2 receptor, or PLA2G2D 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 PLA2G2D-PGD2/DP1 pathway is a useful target for therapeutic interventions.</span><br></p><p></p>