Inhaled steroids reduce SARS-CoV-2-related genes in COPD

The chronic lung condition called COPD (chronic obstructive pulmonary disease) increases the risk of severe COVID-19.

Inhaled corticosteroids (ICS) are commonly prescribed to stabilize respiratory function in these patients, but the associated risk of bacterial infection has daunted some healthcare professionals from using them. Moreover, in vitro, studies show that they have an immunosuppressive effect on cells exposed to viruses. There is no evidence to reveal the effects of ICS on either susceptibility to COVID-19 or the severity of infection in patients with COPD.

ICS/LABA vs LABA Monotherapy

A new study published on the preprint server medRxiv* aims to explore the effects of treatment with ICS on the expression of specific genes related to SARS-CoV-2 infection in bronchial epithelial cells in a prospective interventional design. It is known that COPD can upregulate the expression of angiotensin-converting enzyme (ACE2) in the human lungs. However, in vitro, studies show that ICS reduces ACE2 expression. Observational studies have shown that in both asthma and COPD, the use of ICS reduces the concentration of ACE2 mRNA in sputum.

Binding of the coronavirus spike protein(red) to an ACE2 receptor (blue) on a human cell leads to the penetration of the virus in the cell, as depicted in the background. Image Credit: Juan Gaertner / Shutterstock
Binding of the coronavirus spike protein(red) to an ACE2 receptor (blue) on a human cell leads to the penetration of the virus in the cell, as depicted in the background. Image Credit: Juan Gaertner / Shutterstock

In the DISARM study, the researchers randomized 68 volunteers with mild to very severe COPD to receive either ICS along with a long-acting beta-agonist (LABA) or the LABA alone. Most were male, and the degree of blockage of the airways ranged from moderate to severe.

The regimens in the two groups consisted of formoterol/budesonide 12/400 μg twice daily or salmeterol/fluticasone propionate 25/250 μg twice daily), for the first group, and formoterol 12 μg twice daily for the second. Bronchoscopy was performed to obtain bronchial epithelial cell samples from the 6th to 8th generation of bronchi. They then did RNA sequencing to determine the gene expression across the entire transcriptome.

ICS Could Downregulate ACE2 Expression

They found that at baseline, there was no discernible difference in gene expression between the two groups. ACE2 expression declined with age, but was increased in smokers. However, volunteers who received formoterol and budesonide compared to formoterol alone had a lower expression of the ACE2 gene, which is the receptor for the SARS-CoV-2 virus that causes COVID-19, and of the human cell protease gene ADAM17. The LABA only subgroup showed a significantly increased expression of these genes. The subgroup which received the salmeterol/fluticasone therapy showed no significant change relative to baseline levels.

However, when compared to the LABA-only subgroups, both combination therapy groups showed lower expression of ACE2, while ADAM17 expression was lower with the formoterol/budesonide subgroup. This indicates that ICS suppresses the transcription of these genes, say the researchers.

A transcriptome-wide search shows that genes that are upregulated by the LABA-only treatment are suppressed by the combination of ICS/LABA therapy and vice versa. However, both ICS/LABA subgroups showed the same trend in gene expression effects.

ACE2/ADAM17 Genes Related to Innate Immunity Genes

Genes are said to be co-expressed if their transcription levels are correlated. This can allow genes that are active at the same time to be studied for their biological function. The researchers looked at genes expressed simultaneously with important SARS-CoV-2-related genes before treatment. They found that these genes are expressed in synchrony with innate immune response genes, especially those which belong to type I interferon (IFN-1) and antiviral pathways.

While the downregulation of ACE2 should have a protective effect by reducing host cell susceptibility to SARS-CoV-2, this molecule is also an essential counter-regulatory component of the renin-angiotensin-aldosterone system. Its deficiency can, therefore, cause acute lung injury mediated by angiotensin-II/AT1.

Co-expressed Genes Also Downregulated by ICS

The study also shows that the genes which are co-expressed with those genes that are key in SARS-CoV-2 infection are also co-repressed by ICS. This includes genes related to innate immunity and antiviral responses, which also showed significant downregulation with ICS therapy.

ACE2 has been shown to be a potential interferon-stimulated gene (ISG) within epithelial cells. The findings of the current study support this. For instance, viral sensor gene expression correlated well with ACE2 gene expression, including many genes that are part of the IFN-1 pathway. The IFN-1 pathway is essential in triggering an early response to viral infection by a cell. It sets off ISG expression and promotes an antiviral state in the host. It also induces inflammatory cytokines. ACE2 may prevent lung inflammation by angiotensin II/AT1 following viral infection, in its role as an ISG.

Secondly, changes in ACE2 expression are strongly associated with changes in other ISGs. Another finding was that most innate immune response genes correlated with ADAM17 gene expression. This could mean that these genes have a common pathway of transcription, which is affected by ICS.

An early IFN response limits viral infection and lung damage, while a delayed or unregulated IFN response causes severe inflammation and lung damage. COPD patients are already prone to reduced IFN-1 responses after a viral infection, and thus IFN therapy given early might decrease their chances of severe COVID-19. ICS may affect the IFN-1 pathway in the epithelium of the airway.

ADAM17 also induces the shedding of the ACE2 ectodomain to produce soluble ACE2, in the presence of the viral spike protein. It also induces the shedding of the IL-6 receptor to trigger the trans-signaling IL-6 pathway.

Implications

The researchers pointed out that for the first time, this study shows that ICS therapy affects important genes in the SARS-CoV-2 pathway.

They say, “Their relation to important antiviral response genes may have critical implications for SARS-CoV-2 susceptibility or COVID-19 severity in this vulnerable population.”

They agree, therefore, with the international consensus that ICS should be continued in COPD patients if otherwise clinically indicated, to achieve optimal symptom control and reduce the risk of worsening disease.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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