GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection.

RATIONALE: Severe viral respiratory infections are often characterised by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain poorly understood. 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 severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. RESULTS: Oxidised 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 infection. Both IAV and SARS-CoV-2 infection 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 oxidised cholesterols 25-hydroxycholesterol (25-OHC) 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 significantly attenuated the severity of SARS-CoV-2 infection and viral loads. Analysis of single cell RNASeq data on bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed that CH25H, CYP7B1 and GPR183 are significantly upregulated in macrophages during COVID-19. CONCLUSION: This study demonstrates that oxysterols drive inflammation in the lung via GPR183 and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections.

Crisis and extended realities: remote presence in the time of COVID-19

The transformative influence of the COVID-19 pandemic on remote forms of communication has been a frequent theme in popular discourse during 2020, but any lingering transformation of what we do at a distance will rely on convincing and accessible forms of remote presence and interaction. Embodied communication is difficult to simulate, and this discussion examines current and emerging extended reality (XR)?based communication tools in a range of contexts to discover what role they may play in a future where crises of mobility are likely to grow more frequent and protracted. We define XR and its current uses, then examine key terms used to conceptualise it such as ?presence? and ?social presence?, before highlighting social challenges of remote presence and ethical considerations that accompany its use, particularly how the technology might (or fail to) address important social problems, support education and have relevance to the future of work.