Identification of common genes in COVID-19 and COPD

The pandemic with coronavirus disease 2019 (COVID-19) has caused several waves of infections in many regions of the world, so strong that they overwhelm local health services. In this new situation, faced with an unknown virus, the need is to develop clinical guidelines that help recognize and manage critical COVID-19. Meanwhile, conditions such as chronic obstructive pulmonary disease (COPD) are associated with a markedly increased risk of death from community pneumonia.

Study: Identification of COVID-19 and COPD common key genes and pathways using a protein-protein interaction approach.  Image credit: Siwakorn TH / ShutterstockStudy: Identification of COVID-19 and COPD common key genes and pathways using a protein-protein interaction approach. Image credit: Siwakorn TH / Shutterstock

A new pre-print available on bioRxiv* The preprint server uses computational algorithms to read the relationship between these two conditions that cause similar results. Based on protein-protein interactions (PPIs), the paper shows the presence of ten genes that overlap between the two diseases, also shared by several other deadly and disabling diseases.

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has led to approximately five million deaths so far. Older adults are by far the worst affected by COVID-19, with this disease accounting for 80% of all deaths in the age group 65 years and over.

Interestingly, this age group also has the highest risk of COPD. In this condition, which is found in one tenth of people over the age of 40, airflow is restricted, mainly caused by chronic bronchitis or emphysema. Many genetic and environmental factors play a role in the incidence of this disease, including irritating chemical inhalation or smoking, although only about one-fifth of smokers have COPD.

While COPD patients rarely receive COVID-19, the risk of death is much higher than non-COPD patients. Accordingly, recommendations have recently been made to update the diagnosis and treatment protocols for COPD.

Independent of COVID-19, COPD is responsible for the third largest number of deaths in the world. Considered a polygenic condition, it makes its victims susceptible to serious illness and death after the onset of a cytokine storm by SARS-CoV-2 infection.

The latter only causes symptoms after about five days, with death, if it occurs, occurring on average 14 days later, depending on the patient’s age and immunity.

However, COPD is a condition that can be treated if it cannot be cured, with current therapies that are able to maintain a high quality of life and keep the patient safe from other respiratory diseases. When coexisting with COVID-19, the airways suffer due to pre-existing lung damage. Thus, severe COVID-19 is four times more likely in such patients.

COPD patients have higher levels of the viral entry receptor, the angiotensin-converting enzyme 2 (ACE2), just like smokers.

What did the study show?

The researchers constructed a PPI network using available data on 5.5,500 COVID-19 and 296 COPD gene expression profiles to elucidate the genes involved in such complicated conditions.

They first identified 248 overlapping genes, ten of which turned out to be the most common genes. These are implicated in cell-cell communication and metabolism, development, response to stimuli, and biological regulation. These genes are mostly also involved in pathways implicated in malaria, trypanosomiasis, and inflammatory bowel disease (IBD).

The interleukin 10 (IL 10) gene is the first common gene, or hub gene, that expresses a regulatory cytokine that modulates the inflammatory response. It is markedly upregulated in connection with the cytokine storm in severe COVID-19 patients admitted to the intensive care unit (ICU).

However, it is low in patients with COPD who have dramatic airway inflammation. IL-10 thus serves as a marker of the severity of the disease and is useful for monitoring treatment.

The study similarly elucidates the role of Toll-like receptor 4 (TLR4), expressed by several immune cells and found to be necessary for initiating inflammatory responses. When it rises too much, hyperinflammation can occur.

The TLRs are driven by the recognition of viral RNA or dsDNA intermediates (called pathogen-associated molecular patterns (PAMPs), which are formed from the viral genome and are recognized by pattern recognition receptors, especially the TLRs, which trigger additional inflammatory antiviral cascades that eventually clear the virus.

TLR4 is found to have the highest PPI with the viral nail protein compared to other TLRs. SARS-CoV-2 has been shown to increase the expression of interferon-stimulated genes (ISGs) in the airways. However, the higher levels of ISG expression may also cause greater ACE2 expression. Research shows how lung surfactants block infection by TLR4 binding and activation.

Other hub genes include Tumor necrosis factor (TNF), an important inflammatory mediator that is elevated in acute inflammation due to viral infection and chronic or systemic inflammation. High TNF levels are found in patients with COPD and patients with acute COVID-19 and COPD.

Fourth, IL6 is a potent inflammatory cytokine with several effects in the inflammatory cascade. It is produced by many cell types, including epithelial airway cells and alveolar macrophages. High IL6 levels are associated with poorer lung function and an accelerated rate of deterioration and skeletal muscle weakness in COPD.

IL8, also known as CXCL8, is a mediator of neutrophil tracking and is implicated in inflammatory processes, especially after viral infections. Respiratory muscle weakness in patients with COPD can be partly traced to IL8 activity, with increases in the level of this cytokine during COPD exacerbations. High CXCL8 levels are suggested to be the cause of death in severe COVID-19.

IL4 is an activator of the JAK-STAT pathway that drives inflammation and mediates airway hyperresponse, a central COPD element.

The seventh hub gene is ICAM1, an intercellular adhesion molecule that is overproduced during early inflammation, causing premature release of neutrophils. This molecule is elevated in COPD patients. With moderate to severe COVID-19, ICAM1 levels are high and rising, but declining in convalescence.

This may mean that these molecules are markers of COVID-19 severity. In addition, they also trigger coagulation errors. The four intracellular binding sites for SARS-CoV-2 in human cells are highly expressed in COPD patients.

The eighth hub gene is interferon-gamma (IFN-γ). This is known to be a key risk factor for COVID-19 patients with lung disease. COPD patients have a more than five times higher risk of severe COVID-19

TLR2 is the ninth hub gene, associated with a decrease in lung function and signs of inflammation in sputum, indicating its role in COPD pathogenesis and exacerbation. It is also known to recognize SARS-CoV-2 particles and may be part of the infection-pulmonary embolism pathway.

The last of the hub genes is IL18, which is thought to be linked to the abnormal inflammatory pathways in COPD. Anti-IL 18 antibodies neutralize damage and inflammation caused by COPD in preclinical models.

What are the implications?

The current study, based on a network of PPIs, highlighted the hub genes responsible for the virulence of COVID-19. The system is complex, and current research results help unravel the inflammatory response to the virus. Following viral stimulation of the cytoplasmic inflammasome NLRP3 in macrophages and T helper cell type 1 (Th1), there is an increased production of IL 18, which contributes to the virulence of the infection and the severity of the disease,

In summary, COPD patients with severe COVID-19 showed higher serum levels of inflammatory cytokines such as IL 2, IL 6, IL 8, IL 10 and TNF-α, indicating that the immune response may be altered globally. “

These hub genes elevated in patients with both of these conditions may mean that COPD patients who have a higher risk of severe COVID-19 need to be assessed and treated differently.

*Important message

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

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