Study uncovers why PF after severe COVID-19 doesn’t progress
Gene activity imbalance can explain IPF progression, offer insights for therapies
An imbalance in gene activity within two types of immune cells explains why idiopathic pulmonary fibrosis (IPF) progresses but in people who develop lung fibrosis after a severe COVID-19 infection, their lungs get better, a new study finds.
Researchers showed mortality risk in IPF and COVID-19 was tied to the increased activity of seven genes in immune monocytes and decreased activity of 43 genes in immune T-cells. In patients who developed pulmonary fibrosis after having severe COVID-19, this pattern was reversed.
“We believe that the opportunity is to modulate the expression [activity] of genes identified in this study as a way to treat acute COVID-19, post-COVID-19 pulmonary fibrosis and IPF,” Jose Herazo-Maya, MD, the study’s corresponding author and associate professor at the University of South Florida (USF) Health Morsani College of Medicine, said in a university news story.
The study, “Convergent and divergent immune aberrations in COVID-19, post-COVID-19-interstitial lung disease, and idiopathic pulmonary fibrosis,” was published in the American Journal of Physiology – Cell Physiology.
Pulmonary fibrosis is a type of interstitial lung disease (ILD), a group of disorders marked by inflammation and scarring, or fibrosis, in the lungs. This scarring damages the epithelial cells that line the alveoli, or the tiny sacs responsible for gas exchange in the lungs, leading to lung function decline and symptoms that include shortness of breath.
IPF is progressive, with lung scarring, symptoms gradually worsening over time
Pulmonary fibrosis is grouped into several types based on its underlying cause. In IPF, the most common type of pulmonary fibrosis, the specific underlying cause is unknown. Like other forms of the disease, IPF is progressive, meaning that lung scarring and symptoms gradually worsen over time.
Severe COVID-19 can also lead to pulmonary fibrosis. However, unlike IPF, many people with this form of fibrosis get better.
“The importance of this finding is that pulmonary fibrosis after COVID-19 tends to resolve, while in idiopathic pulmonary fibrosis (IPF) it always progresses,” said Herazo-Maya, who is also the director of USF’s Ubben Center for Pulmonary Fibrosis Research. “We need to learn about the factors associated with pulmonary fibrosis resolution and apply it to non-resolving forms of pulmonary fibrosis.”
To that end, a team of researchers led by Herazo-Maya collected whole blood from 227 people with COVID-19, post-COVID-19 ILD, IPF, and healthy controls. They specifically analyzed the signatures of 50 genes known to predict IPF and COVID-19 mortality and the levels of several biomarkers.
Analyses revealed three genomic risk profiles for COVID-19 based on the 50-gene signature corresponding to a low, intermediate, or high mortality risk. Among the 50 genes, the excessive activity, or overexpression, of seven of them was significantly linked to a high mortality risk.
To determine the cellular source of the seven-gene signature that predicted COVID-19 mortality, the team then performed single-cell RNA sequencing on immune cells taken from patients and controls. This technique provides a snapshot of gene activity at the individual cell level, helping to pinpoint which cells contribute to the gene signature.
Single-cell RNA sequencing used to study entire human genome
“We used single-cell RNA sequencing, a novel technique that allows us to study the entire human genome in each single cell from patients,” Herazo-Maya said.
COVID-19 mortality risk was linked to the increased expression of these seven genes in a subset of immune cells called monocytic myeloid-derived suppressor cells, here dubbed 7Gene-M-MDSCs.
At the same time, the high-risk COVID-19 group had decreased expression of 43 genes in certain subsets of immune T-cells. On the contrary, people with post-COVID-19 ILD had increased expression of these 43 genes in their cells, while low expression persisted in IPF patients.
Overall, results indicated that mortality risk in IPF and COVID-19 is characterized by a genomic imbalance in immune monocyte and T-cell subsets, a “thought-provoking finding,” according to researchers.
“What this means is that 7-Gene-M-MDSC are associated with increased risk of COVID-19 mortality, but if you survive severe COVID-19 and end up having pulmonary fibrosis as a result, the pulmonary fibrosis is self-limited and not progressive,” said Bochra Tourki, PhD, the study’s first author and a member of Herazo-Maya’s team. “We think this is because of the disappearance of the 7-Gene-M-MDSC and the resurgence of T cell responses.”
Conversely, an increase in 7Gene-M-MDSCs and a decrease in T-cell subsets may have detrimental effects on COVID-19 and IPF. In this scenario, blocking gene expression in monocytes and/or boosting gene expression in certain T-cells may turn IPF into a form of pulmonary fibrosis that can be treated.
“What we found in this study were the key immune elements (cells and genes) that may explain resolution versus progression of pulmonary fibrosis,” Herazo-Maya said. “Strategies aiming at modulating the cells that cause these genes to change may lead to novel therapies that could improve COVID-19 survival.”
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