Lung remodeling regions in long-term Covid-19 feature basal epithelial cell reprogramming

Respiratory viruses, including SARS-CoV-2, can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, we examined a series of consecutive fatal cases of Covid-19 that came to autopsy at 27-51 d after hospital admission. In each patient, we identify a stereotyped bronchiolar-alveolar pattern of lung remodeling with basal epithelial cell hyperplasia, immune activation, and mucinous differentiation. Remodeling regions also feature macrophage infiltration and apoptosis and a marked depletion of alveolar type 1 and 2 epithelial cells. This entire pattern closely resembles findings from an experimental model of post-viral lung disease that requires basal-epithelial stem cell growth, immune activation, and differentiation. Together, the results provide evidence of basal epithelial cell reprogramming in long-term Covid-19 and thereby yield a pathway for explaining and correcting lung dysfunction in this type of disease.

[1]  Daniel S. Chertow,et al.  Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease , 2022, American journal of respiratory and critical care medicine.

[2]  W. Guan,et al.  Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease , 2022, American journal of physiology. Lung cellular and molecular physiology.

[3]  Fabian J Theis,et al.  SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis , 2021, Cell.

[4]  C. Yao,et al.  Epithelial plasticity and innate immune activation promote lung tissue remodeling following respiratory viral infection , 2021, bioRxiv.

[5]  Samantha A. Morris,et al.  Basal-epithelial stem cells cross an alarmin checkpoint for post-viral lung disease. , 2021, The Journal of clinical investigation.

[6]  M. Netea,et al.  The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity , 2021, The Lancet Respiratory Medicine.

[7]  Timothy L. Tickle,et al.  COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets , 2021, Nature.

[8]  André F. Rendeiro,et al.  A molecular single-cell lung atlas of lethal COVID-19 , 2021, Nature.

[9]  P. Laterre,et al.  Increased Angiotensin-Converting Enzyme 2 and Loss of Alveolar Type II Cells in COVID-19–related Acute Respiratory Distress Syndrome , 2021, American journal of respiratory and critical care medicine.

[10]  Y. Tesfaigzi,et al.  Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: A conundrum for COVID-19 pathogenesis , 2021, PloS one.

[11]  Lei Liu,et al.  Analysis of pathological changes in the epithelium in COVID-19 patient airways , 2021, ERJ Open Research.

[12]  Shamus P. Keeler,et al.  TLR3-Activated Monocyte-Derived Dendritic Cells Trigger Progression from Acute Viral Infection to Chronic Disease in the Lung , 2021, The Journal of Immunology.

[13]  Benjamin Bowe,et al.  High-dimensional characterization of post-acute sequelae of COVID-19 , 2021, Nature.

[14]  Grace X. Y. Zheng,et al.  Progenitor identification and SARS-CoV-2 infection in human distal lung organoids , 2020, Nature.

[15]  Colin Smith,et al.  Tissue-Specific Immunopathology in Fatal COVID-19 , 2020, American journal of respiratory and critical care medicine.

[16]  Ting Zhang,et al.  Single‐cell analysis identified lung progenitor cells in COVID‐19 patients , 2020, Cell proliferation.

[17]  M. Mino‐Kenudson,et al.  Lung Histopathology in COVID-19 as Compared to SARS and H1N1 Influenza: A Systematic Review , 2020, Chest.

[18]  C. del Rio,et al.  Long-term Health Consequences of COVID-19. , 2020, JAMA.

[19]  Jacques Fellay,et al.  Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 , 2020, Science.

[20]  Shamus P. Keeler,et al.  Group 2 Innate Lymphoid Cells Must Partner with the Myeloid–Macrophage Lineage for Long-Term Postviral Lung Disease , 2020, The Journal of Immunology.

[21]  A. Saqi,et al.  Distinct stem/progenitor cells proliferate to regenerate the trachea, intrapulmonary airways and alveoli in COVID-19 patients , 2020, Cell Research.

[22]  C. von Kalle,et al.  COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis , 2020, Nature Biotechnology.

[23]  Zhènglì Shí,et al.  Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients , 2020, EBioMedicine.

[24]  P. Wolters,et al.  Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells , 2020, bioRxiv.

[25]  T. Uyeki,et al.  Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States , 2020, Emerging infectious diseases.

[26]  Jie Dong,et al.  Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients , 2020, Cell Host & Microbe.

[27]  D. Meyerholz,et al.  Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract , 2020, bioRxiv.

[28]  Subha Ghosh,et al.  COVID-19 Autopsies, Oklahoma, USA , 2020, American journal of clinical pathology.

[29]  Shamus P. Keeler,et al.  Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost , 2019, The Journal of Immunology.

[30]  Shamus P. Keeler,et al.  Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants , 2018, The Journal of Immunology.

[31]  R. Chivukula,et al.  A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury. , 2018, The American journal of pathology.

[32]  Samriddha Ray,et al.  Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection , 2016, Stem cell reports.

[33]  M. Colonna,et al.  TREM-2 promotes macrophage survival and lung disease after respiratory viral infection , 2015, The Journal of experimental medicine.

[34]  Mark R. Looney,et al.  Lineage-negative Progenitors Mobilize to Regenerate Lung Epithelium after Major Injury , 2014, Nature.

[35]  R. Pierce,et al.  Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. , 2013, The Journal of clinical investigation.

[36]  M. Holtzman,et al.  IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. , 2012, The Journal of clinical investigation.

[37]  M. Holtzman.  Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. , 2012, The Journal of clinical investigation.

[38]  R. Pierce,et al.  Oxidative damage to nucleic acids in severe emphysema. , 2009, Chest.

[39]  Jeffrey D. Morton,et al.  Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease , 2008, Nature Medicine.

[40]  R. Pierce,et al.  Triggering Receptor Expressed on Myeloid Cells‐2 Expression Tracks With M2‐Like Macrophage Activity and Disease Severity in COPD , 2018, Chest.