Efferocytosis of apoptotic bodies drives SARS-CoV-2 infection and macrophage inflammation.

SARS-CoV-2 typically utilises host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. Despite low ACE2 expression, monocyte-derived macrophages, the predominant lung macrophage during severe COVID-19, are often found with SARS-CoV-2 in infected lungs. As macrophage inflammation and cytokine storm are key immunopathological events that drive severe COVID-19, insights into mechanisms underlying viral entry into macrophages are critical to devise novel COVID-19 therapies. Mounting evidence supports that COVID-19 pathogenesis is associated with apoptosis, a type of programmed cell death which releases large extracellular vesicles called apoptotic bodies (ApoBDs). Here, we show that ApoBDs from SARS-CoV-2-infected cells carried infectious virions. Macrophages efferocytose these ApoBDs, enabling SARS-CoV-2 entry and pro-inflammatory responses including inflammasome and NF-κB signalling. To demonstrate targetability of this ApoBD efferocytosis-mediated viral entry, we screen for inhibitors of SARS-CoV-2-induced ApoBD formation and identified T-type voltage-gated calcium channel (T-channel) blockers. Mechanistically, T-channel blockers impair the extracellular calcium influxes required for ApoBD biogenesis. Importantly, blockade of ApoBD formation by T-channel blockers is able to limit cell-to-cell viral transmission, macrophage inflammation and lung immunopathology. Our discovery reveals a novel route for SARS-CoV-2 infection and cytokine storm induction, expanding our understanding of COVID-19 pathogenesis and demonstrating a therapeutic target for infectious diseases.