Thanh Kha Phan, Dylan Sheerin, Bo Shi, Ngee K. Chua, Sriram Gummadi, Merle Dayton, Liana Mackiewicz, Ana Maluenda, Dilara C. Ozkocak, Georgia K. Atkin‐Smith, Nashied Peton, Ching‐Seng Ang, Omar Audi, Quan Thinh Le, Thu Uyen Tran, Tuong-Khanh My Tu, Rochelle Tixeira, George W. Ashdown, Kathryn C. Davidson, Pamali Fonseka, Rebecca Feltham, Marcel Doerflinger, Mark D. Hulett, Anna K. Coussens, Ivan K. H. Poon
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.