Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection

Abstract

The SARS-CoV-2 pandemic has inspired renewed interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS) following infection. However, the pathogenesis of ARDS following SRAS-CoV-2 infection remains largely unknown. In the present study, we examined apoptosis in postmortem lung sections from COVID-19 patients and in lung tissues from a non-human primate model of SARS-CoV-2 infection, in a cell-type manner, including type 1 and 2 alveolar cells and vascular endothelial cells (ECs), macrophages, and T cells. Multiple-target immunofluorescence assays and Western blotting suggest both intrinsic and extrinsic apoptotic pathways are activated during SARS-CoV-2 infection. Furthermore, we observed that SARS-CoV-2 fails to induce apoptosis in human bronchial epithelial cells (i.e., BEAS2B cells) and primary human umbilical vein endothelial cells (HUVECs), which are refractory to SARS-CoV-2 infection. However, infection of co-cultured Vero cells and HUVECs or Vero cells and BEAS2B cells with SARS-CoV-2 induced apoptosis in both Vero cells and HUVECs/BEAS2B cells but did not alter the permissiveness of HUVECs or BEAS2B cells to the virus. Post-exposure treatment of the co-culture of Vero cells and HUVECs with a novel non-cyclic nucleotide small molecule EPAC1-specific activator reduced apoptosis in HUVECs. These findings may help to delineate a novel insight into the pathogenesis of ARDS following SARS-CoV-2 infection.

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

“…Extracellular proteases, such as furin and cathepsins, promote SARS-CoV-2 infection over other coronaviruses, as demonstrated by others (Bestle et al, 2020;Dessie and Malik, 2021;Huffman et al, 2021;Murgolo et al, 2021;Raghav et al, 2021;Rossi et al, 2020;Watzky et al, 2021;Zhang et al, 2021), and our current data support these findings by identifying a novel mechanism of virus-mediated inflammation. Our data that ATP, PGE 2 , and IL1b are highly concentrated in the BAL obtained from COVID-19 individuals is exciting but needs to be considered carefully due to the fact that during the evolution of the disease, significant apoptosis of lung cells occurs (Liu et al, 2021). This apoptosis then contributes to the nonspecific release of ATP.…”

Post-mortem lung tissue: the fossil record of the pathophysiology and immunopathology of severe COVID-19

“…Marked apoptosis has been demonstrated in the alveolar and vascular compartments of human COVID-19 lung tissue by use of the TUNEL assay. 34 Application of the TUNEL assay to lung tissue from a non-human primate model of COVID-19 disease showed co-localisation of cytochrome C and Fas ligand, markers of the intrinsic and extrinsic apoptotic pathways, potentially implicating both pathways in the disease process. 34 Formation of the inflammasome is understood to activate cell death pathways, including pyroptosis and apoptosis, 35 and immunofluorescence has been used to demonstrate the expression of inflammasome-associated proteins in COVID-19 lung tissue, which was greater than in control lung tissue and predominantly localised within leucocytes.…”

“… 34 Application of the TUNEL assay to lung tissue from a non-human primate model of COVID-19 disease showed co-localisation of cytochrome C and Fas ligand, markers of the intrinsic and extrinsic apoptotic pathways, potentially implicating both pathways in the disease process. 34 Formation of the inflammasome is understood to activate cell death pathways, including pyroptosis and apoptosis, 35 and immunofluorescence has been used to demonstrate the expression of inflammasome-associated proteins in COVID-19 lung tissue, which was greater than in control lung tissue and predominantly localised within leucocytes. 36 Bharat and colleagues 37 applied immunofluorescence to visualise the extracellular matrix of post-mortem or explanted lung tissue, noting COVID-19-associated fibrotic injury resembling end-stage pulmonary fibrosis.…”

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

“…The role of cell death and apoptosis in COVID-19 is a topic still under investigation. Intrinsic and extrinsic pathways are induced by SARS-CoV-2 infection [ 99 ]. In this field, studies on SARS-CoV-2 have mirrored those on SARS-CoV.…”