A study carried out at the University of São Paulo (USP) can help to understand why the mortality rate by new coronavirus greater among people who suffer from chronic health problems, such as hypertension, diabetes or chronic obstructive pulmonary disease (COPD).
According to the conclusions, released on the medRxiv platform, changes in metabolism caused by these diseases can trigger a series of biochemical events that lead to an increase in the expression of the ACE-2 gene, responsible for encoding a protein to which the virus connects to infect lung cells.
“Our hypothesis is that the increase in the expression of ACE-2 and other genes that facilitate infection – including TMPRSS2 and FURIN – causes these patients to have a greater number of cells affected by the SARS-CoV-2 virus and, consequently, a more severe picture of the disease. But it is something that still needs to be confirmed by experimental studies ”, says Helder Nakaya, professor at the Faculty of Pharmaceutical Sciences (FCF-USP) and research coordinator, supported by FAPESP (São Paulo Research Foundation).
The findings, according to the researcher, may help in the identification of molecular targets for the development of drugs.
As Nakaya explains, the ACE-2 gene (ECA-2 in Portuguese) expresses the messenger RNA that guides the production of the angiotensin-converting enzyme 2 – a molecule that integrates the so-called renin-angiotensin-aldosterone system, responsible for controlling blood pressure.
“After the SARS outbreak [síndrome respiratória aguda grave] in 2003, scientists discovered that the ACE-2 gene was crucial for the virus to enter human cells. Now, the same has been observed for the new coronavirus. For this reason, we decided to investigate whether its expression was altered in patients with chronic diseases ”, says the researcher.
Bioinformatics
The first step of the investigation was to seek Medline database – which covers almost 5,000 journals published in more than 70 countries and is maintained by the United States National Library of Medicine – all scientific articles related to diseases considered of interest by the group, including hypertension, diabetes, cardiovascular diseases, COPD, cancer lung disease, chronic renal failure, autoimmune diseases, pulmonary fibrosis, asthma and pulmonary hypertension.
“We identified 8,700 articles and, as it would be impracticable to read them all, we used a text mining tool to filter out only those that contained information about the genes involved in these diseases. We arrived at a set of genes among which was ACE-2, ”says Nakaya to Agência FAPESP.
Next, the researchers re-analyzed transcritomic data (relative to the level of RNA expressed by the more than 25,000 human genes) in more than 700 lung samples available in public repositories, such as the Gene Expression Omnibus (GEO).
“These are freely accessible data collected in previous studies. What we did was to compare the gene expression profile of patients with chronic diseases that affect the lung with that of healthy people, who served as controls. We even compare the profile of smokers and non-smokers ”, explains Nakaya. “The idea was to look at the lungs of people who were not infected with the new coronavirus, but who had diseases that made them more susceptible to severe manifestations of COVID-19 to try to understand what was different.”
According to Nakaya, the meta-analysis revealed that the expression of ACE-2 was, in fact, significantly increased in diseases.
The next step was to find out which other genes had expression profiles similar or inverse to ACE-2.
“This type of correlation analysis helps to guide hypotheses, although it does not allow establishing a causal relationship. So, instead of looking at 500 genes, we can focus on eight whose expression is correlated with that of interest and, in the future, do experiments to find out what happens when they are inhibited or stimulated ”, explains Nakaya.
The group then realized that in the samples with increased ACE-2 expression, some enzymes capable of modifying the functioning of proteins known as histones, which are in the nucleus of cells – linked to DNA – and help to regulate gene expression, were also more expressed. In scientific jargon, this biochemical phenomenon is known as epigenetic modification (when there is a change in the expression pattern of the gene without any change in the DNA).
“Our findings suggest that these chronic diseases change – it is not yet known how – the body’s epigenetic program, making these enzymes more active and, consequently, increasing the expression of ACE-2 and favoring the infection of lung cells by SARS- CoV-2 ”, says Nakaya.
The discovery, according to the researcher, paves the way for the search for compounds capable of inhibiting the activity of some of these histone-modifying enzymes, which could modulate the expression of ACE-2 and thereby protect the lungs of patients.
The article ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19 – still in a pre-print version (not peer-reviewed) – can be read on here.