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

Phan, TK; Sheerin, D; Shi, B; Chua, NK; Gummadi, S; Dayton, M; Mackiewicz, L; Maluenda, A; Ozkocak, DC; Atkin-Smith, GK; Peton, N; Ang, CS; Audi, O; Thinh Le, Q; Tran, TU; Tu, TM; Tixeira, R; Ashdown, GW; Davidson, KC; Fonseka, P; Feltham, R; Doerflinger, M; Hulett, MD; Coussens, AK; Poon, IKH

Author(s): Phan, TK; Sheerin, D; Shi, B; Chua, NK; Gummadi, S; Dayton, M; Mackiewicz, L; Maluenda, A; Ozkocak, DC; Atkin-Smith, GK; Peton, N; Ang, CS; Audi, O; Thinh Le, Q; Tran, TU; Tu, TM; Tixeira, R; Ashdown, GW; Davidson, KC; Fonseka, P; Feltham, R; Doerflinger, M; Hulett, MD; Coussens, AK; Poon, IKH;
Journal Title: Nature Communications
Abstract: 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-kappaB 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.
Publisher: Springer Nature
Keywords: Humans; Efferocytosis; *COVID-19/immunology/virology/pathology; *SARS-CoV-2/physiology; *Macrophages/immunology/virology/pathology; *Apoptosis; Animals; Virus Internalization/drug effects; Inflammation/pathology/immunology; *Extracellular Vesicles/metabolism/immunology; NF-kappa B/metabolism; Angiotensin-Converting Enzyme 2/metabolism; Mice; Signal Transduction; Inflammasomes/metabolism
Research Division(s): Ubiquitin Signalling; Infection and Global Health; Advanced Technology and Biology; Inflammation
PubMed ID: 42297820
Publisher's Version: https://doi.org/10.1038/s41467-026-74363-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-026-74363-8.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-19 01:23:33

Last Modified: 2026-08-14 11:30:42