| Autor: |
Murthy A; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Rodriguez LR; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Dimopoulos T; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Bui S; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Iyer S; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Chavez K; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Tomer Y; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Abraham V; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Cooper C; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Renner DM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; Penn Center for Research on Coronaviruses and Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Katzen JB; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Bentley ID; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States., Ghadiali SN; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.; Department of Biomedical Engineering, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States., Englert JA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States., Weiss SR; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; Penn Center for Research on Coronaviruses and Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States., Beers MF; Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States. |
| Abstrakt: |
COVID-19 syndrome is characterized by acute lung injury, 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, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (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 used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population ( Krt8 + and Cldn4 + ). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a 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 lung injury from β-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure. NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that β-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure. |
