TY - JOUR T1 - Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection JF - bioRxiv DO - 10.1101/2022.06.14.496214 SP - 2022.06.14.496214 AU - Cheng Xiang Foo AU - Stacey Bartlett AU - Keng Yih Chew AU - Minh Dao Ngo AU - Helle Bielefeldt-Ohmann AU - Buddhika Jayakody Arachchige AU - Benjamin Matthews AU - Sarah Reed AU - Ran Wang AU - Matthew J. Sweet AU - Lucy Burr AU - Jane E. Sinclair AU - Rhys Parry AU - Alexander Khromykh AU - Kirsty R. Short AU - Mette Marie Rosenkilde AU - Katharina Ronacher Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/16/2022.06.14.496214.abstract N2 - Rationale Severe viral respiratory infections are often characterized by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain elusive.Objectives To identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity.Methods Preclinical murine models of influenza virus and SARS-CoV-2 infection.Results Oxidized cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte-macrophage infiltration to the lung during influenza virus (IAV) and SARS-CoV-2 infections. Both IAV and SARS-CoV-2 infections upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidized cholesterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of GPR183, or treatment with a GPR183 antagonist, reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist also significantly attenuated the severity of SARS-CoV-2 infection by reducing weight loss and viral loads.Conclusion This study demonstrates that oxysterols drive inflammation in the lung and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections.Author Summary Viral infections trigger oxysterol production in the lung, attracting macrophages via GPR183. Blocking GPR183 reduced inflammation and disease severity in SARS-CoV-2 infection, making GPR183 a putative target for therapeutic intervention.Competing Interest StatementKRS is consultant for Sanofi, Roche and NovoNordisk. MMR is co-founder of Antag Therapeutics and of Synklino. The opinions and data presented in this manuscript are of the authors and are independent of these relationships. ER -