Like priming a pump, cells damaged by chronic lung disease can result in severe COVID

Date:
July 14, 2021
Source:
The Translational Genomics Research Institute
Summary:
New research suggests that 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.



FULL STORY ==========================================================================
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 today 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, Ph.D., 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, representing more than
80 institutions worldwide, also contributed to this study.

In addition, older-age, male-gender, smoking, and comorbidities 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, M.D., 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, Ph.D.,
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.

Significant contributions to this study were made by: Vanderbilt
University Medical Center, Yale School of Medicine, Harvard Medical
School, Baylor College of Medicine, and the Department of Veterans
Affairs Medical Center. Plus several institutes in the UK, including:
London's Imperial College, Royal Brompton and Harefield National Health
System Foundation Trust, Edinburgh University Medical School, and the
Royal Infirmary of Edinburgh.

Major funding for this study -- Chronic lung diseases are associated
with gene expression programs favoring SARS-CoV-2 entry and severity
-- was provided by the National Institutes of Health, the Department
of Defense, the Department of Veterans Affairs, and the Doris Duke
Charitable Foundation.

========================================================================== Story Source: Materials provided by The_Translational_Genomics_Research_Institute. Original written by Steve Yozwiak. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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) DOI:
10.1038/s41467-021-24467-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210714110430.htm

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