The results of a study by an international scientific team co-led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, suggest that — like pouring water atop a wellhead before pumping — the airway cells of patients with chronic lung diseases are “primed” for infection by the COVID-19 virus, resulting in more severe symptoms, poorer outcomes, and a greater likelihood of death.

The study — published in Nature Communications — details the genetic changes caused by chronic lung disease in the molecular makeup of a variety of cells, including the epithelial cells that line the lung and airways. The study details how those changes can help enable SARS-CoV-2, the virus that causes COVID-19, to enter the body, replicate and trigger an out-of-control immune response that fills the lungs with fluids and often results in patients needing respirators and lengthy hospitalizations.

The team used single-cell RNA sequencing technology to spell out the genetic code of 611,398 cells from various data bases, representing those with both healthy (control) lungs and those with chronic lung disease. Sequencing and analysis allowed researchers to identify molecular characteristics that may account for worse COVID-19 outcomes.

“Our results suggest that patients with chronic lung disease are molecularly primed to be more susceptible to infection by SARS-CoV-2,” said Nicholas Banovich, PhD, an Associate Professor in TGen’s Integrated Cancer Genomics Division, and one of the study’s senior authors. Dr. Banovich is a leading participant in the Human Cell Atlas Lung Biological Network, whose dozens of members — including McGowan Institute for Regenerative Medicine affiliated faculty member Mauricio Rojas, MD, Professor of Internal Medicine and the Associate Vice Chair of Research, Department of Internal Medicine, in the Division of Pulmonary, Critical Care, & Sleep Medicine of the Davis Heart & Lung Research Institute at The Ohio State University — representing more than 80 institutions worldwide, also contributed to this study.

In addition, older-age, male-gender, smoking, and co-morbidities such as high blood pressure, obesity and diabetes, are all COVID-19 risk factors that are exacerbated by chronic lung diseases, such as Chronic Obstructive Pulmonary Disease (COPD), Interstitial Lung Disease (ILD), and especially Idiopathic Pulmonary Fibrosis (IPF), a progressive scaring and stiffening of the lung tissue.

“It was recognized early in the pandemic that patients with chronic lung diseases were at particularly high risk for severe COVID-19, and our goal was to gain insight into the cellular and molecular changes responsible for this,” said Jonathan Kropski, MD, Associate Professor of Medicine and Cell and Developmental Biology at Vanderbilt University Medical Center, and a co-senior author of the study.

Changes in lung cells and immune cells

Researchers specifically searched for changes in AT2 cells, a major lung epithelial cell type, focusing on cellular pathways and expression levels of genes associated with COVID-19. They established a “viral entry score,” a composite of all genes associated with SARS-CoV-2 and found higher scores among cells from patients with chronic lung disease.

They also explored changes in immune cells and discovered dysregulated gene expression associated with hyper-inflammation and with sustained cytokine production, two signature symptoms of severe SARS-CoV-2 infection. So-called cytokine storms in COVID-19 patients unleash a cascade of immune cells that flood the lungs, causing severe organ damage.

“The genetic changes in immune cells, especially in specialized white blood cells known as T cells, may diminish the patient’s immune response to viral infection and lead to higher risk of severe disease and poor outcomes in patients with chronic lung disease,” said Linh Bui, PhD, a post-doctoral fellow in Dr. Banovich’s lab, and one of the study’s lead authors.

“Our data suggest that the immune microenvironment at both the molecular and cellular levels in lungs damaged by chronic diseases may promote severe COVID-19,” Dr. Bui said.

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Translational Genomics Research Institute (TGen)

Science Daily

Abstract (Linh T. Bui, Nichelle I. Winters, Mei-I Chung, Chitra Joseph, Austin J. Gutierrez, Arun C. Habermann, Taylor S. Adams, Jonas C. Schupp, Sergio Poli, Lance M. Peter, Chase J. Taylor, Jessica B. Blackburn, Bradley W. Richmond, Andrew G. Nicholson, Doris Rassl, William A. Wallace, Ivan O. Rosas, R. Gisli Jenkins, Naftali Kaminski, Jonathan A. Kropski, Nicholas E. Banovich, Alexander V. Misharin, Alexander M. Tsankov, Avrum Spira, Pascal Barbry, Alvis Brazma, Christos Samakovlis, Douglas P. Shepherd, Emma L. Rawlins, Fabian J. Theis, Jennifer Griffonnet, Haeock Lee, Herbert B. Schiller, Paul Hofman, Joseph E. Powell, Joachim L. Schultze, Jeffrey Whitsett, Jiyeon Choi, Joakim Lundeberg, Naftali Kaminski, Jonathan A. Kropski, Nicholas E. Banovich, Jose Ordovas-Montanes, Jayaraj Rajagopal, Kerstin B. Meyer, Mark A. Krasnow, Kourosh Saeb‐Parsy, Kun Zhang, Robert Lafyatis, Sylvie Leroy, Muzlifah Haniffa, Martijn C. Nawijn, Marko Z. Nikolić, Maarten van den Berge, Malte Kuhnemund, Charles-Hugo Marquette, Michael Von Papen, Oliver Eickelberg, Orit Rosenblatt-Rosen, Paul A. Reyfman, Dana Pe’er, Peter Horvath, Purushothama Rao Tata, Aviv Regev, Mauricio Rojas, Max A. Seibold, Alex K. Shalek, Jason R. Spence, Sarah A. Teichmann, Stephen Quake, Thu Elizabeth Duong, Tommaso Biancalani, Tushar Desai, Xin Sun, Laure Emmanuelle Zaragosi. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity. Nature Communications, 2021; 12 (1).)