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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

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  • 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

摘要

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.