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Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARSCoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational Q2 drug combinations for effective treatment of a virus that affects multiple organ systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212003 | GEO | 2023/06/13

REPOSITORIES: GEO

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Project description:Covid-19 syndrome is characterized by an acute lung injury phenotype marked by hypoxemic respiratory failure and high mortality. Alveolar Type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, SARS-CoV-2 and other members of the b coronavirus genus induces an ER stress response in vitro however the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were employed– mouse hepatitis virus-1 (MHV-1) in A/J mice and a C57BL6/j adapted SARS-CoV-2 strain. MHV-1 infected mice exhibited dose-dependent weight loss through Day 8 (8dpi) with histological evidence of distal lung injury accompanied by elevated BALF cell counts and total protein. AT2 cells isolated at 4dpi and 8dpi showed evidence of both viral infection and increases in Bip /GRP78 expression, consistent with activation of the unfolded protein response (UPR). AT2 UPR signaling included elevations in spliced XBP-1 indicating activation of IRE1a signaling as well as a biphasic response in PERK signaling mark by phosphorylated eIF2a protein levels and expression of Atf4, Ppp1r15a, and Ddit3. Viral UPR activation was accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B, SP-C) content, increases in surfactant surface tension, and emergence of a re-programmed epithelial cell population (Krt8+, Cldn4+, and Gdf15+) which was attenuated by treatment with the IRE1a inhibitor OPK711. As proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that hypoxic respiratory failure from b-coronavirus infection results from an aberrant AT2 cell host response activating multiple ER stress pathways, altering surfactant metabolism / function, and changing AT2 endophenotypes offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and hypoxemic respiratory failure.

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Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

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