Ackr1-deficient mice are protected from lethal SARS-CoV-2 challenge

Abstract

Abstract To date, there have been more than 613 million confirmed cases of COVID-19, with over 6 million deaths worldwide. In severe cases, the causative agent of the COVID-19, SARS-CoV-2, induces acute respiratory distress syndrome. To study the roles of chemokine pathways during COVID-19 pathogenesis, we performed an infection screen in mice deficient in chemokine ligands and receptors using the mouse-adapted strain of the virus. Weight loss and death were recorded for 2 weeks after infection of wild type mice, and mice genetically deficient for Ccr2, Ccr5, Ccr6, Cxcr3, Cxcr6, Cxcl10 or the atypical chemokine receptor Ackr1. Acute weight loss was observed in all infected mouse strains; however, Ackr1−/−mice uniquely displayed markedly increased survival compared to wild type mice. ACKR1 (also known as the Duffy antigen receptor for chemokines) is a non-signaling receptor expressed on endothelial cells, erythrocytes and a subset of neurons that binds to a wide range of chemokines thereby controlling their availability as a scavenger and shaping chemotactic gradients. Comprehensive expression analysis revealed Ackr1 as the most highly induced chemokine receptor in infected lung post-infection. Of note, COVID-19 mortality is disproportionately low in West Africa, overlapping with the geographic distribution of genetic deficiency of erythrocyte ACKR1 due to a single nucleotide polymorphism in the ACKR1 promoter that interrupts binding of GATA-1. Further studies are required to understand the modulation of SARS-CoV-2 pathogenesis by Ackr1 and its potential to explain the trajectory and limited mortality of Covid-19 in Africa and to serve as a potential therapeutic target.