New study reveals the biological mechanisms underlying the greater vulnerability of smokers, diabetics, and people with stroke to severe COVID-19 infection

Worldwide, COVID-19 trends so far indicate that the disease is much more severe in certain groups of individuals, such as those who smoke, are older, or have diabetes. But the causes underlying this trend remain unknown. Now, researchers at the National Institute of Health, Korea, find that the cell surface receptor ACE2, which is the novel coronavirus’ gateway into a cell, increases at various sites in our bodies with smoking, diabetes, and stroke.

In a new study, researchers from Korea discovered that individuals with smoking habits, strokes, and diabetes show higher levels of ACE2, the receptor that binds to the spike protein on the novel coronavirus, putting them at a greater risk of infection.

Photo courtesy: Kateryna Kon from Shutterstock.

 

Over 2020, as the COVID-19 pandemic progressed, it became clear that the virus was more likely to cause severe disease in certain “high-risk” populations, such as older folks, those with diabetes, and people with cardiovascular and cerebrovascular conditions like high blood pressure or stroke. A year into the pandemic, several variants of the virus down the line, this trend continues to hold true. 

But, in this time, while we’ve made considerable progress in terms of understanding the mechanisms by which the virus acts in our bodies, we have not been able to definitively find out what makes these high-risk populations more vulnerable than everyone else.

Now, a group of researchers from the National Institute of Health, Korea, presents an explanation. Their findings are published in Biochemical and Biophysical Research Communications.

Speaking of their motivations for the study, lead scientist Dr. Young Ho Koh says, “Patients with chronic disease account for about 98.5% of the COVID-19-related mortality in Korea. Scientific study of the underlying causes of this trend are needed to increase understanding and reduce anxiety among the public about groups vulnerable to COVID-19 infection.” This study was supported by the fund (2020-NI-024-00) from Research of Korea Centers for Disease Control and Prevention.

The scientists began with a key finding related to how the novel coronavirus causes infection in our body. The virus’ name comes from the fact that its shell is covered with spike proteins, which give it a distinctive crown (corona)-like shape. It uses these spikes to bind to a receptor on cell surfaces called “angiotensin-converting enzyme 2” (ACE2) and enters the cells. So, people who have increased expression of ACE2 on some tissue or another in the body are more susceptible to greater infection. 

The ACE2 receptor is found on various bodily tissues, such as the heart, lungs, kidney, intestines, blood vessels, and certain neurons. It is an important enzyme for regulating blood vessel contraction and certain inflammatory responses (immune responses). ACE2 also serves as the entry point into cells for some coronaviruses, including SARS-CoV-2 (the virus that causes COVID-19). And as it turned out, recent clinical studies revealed the presence of the novel coronavirus in tissues other than the lungs and blood vessels, even in postmortem brains. Thus, speaking of how they began the study, Dr. Koh explains, “Since cells that express ACE2 are potentially at risk of novel coronavirus infection, ACE2 expression profiling under various conditions in the brain can help us understand the process of COVID-19 infection.”

Dr. Koh's research group conducted a series of experiments. An mRNA sequencing of brain tissues from rat models with ischemic stroke (where a blood vessel has a blockage) in the brain showed an increased expression of ACE2. Further, human brain microvessel and astrocyte (a type of neuron) cells exposed to cigarette smoke extract showed greatly increased ACE2 expression. In addition, a comparison of human aortic endothelial cells of patients with types 1 and 2 diabetes and those of healthy people showed higher ACE2 expressions in the cells of those with diabetes. Finally, analysis of the brain tissues of mice with type 2 diabetes showed increased ACE2 expression as well.

These findings are preliminary and remain to be verified clinically, but undoubtedly, they are one of the first significant steps towards understanding why individuals with smoking habits, diabetes, and stroke are more vulnerable to the severe symptoms of COVID-19, such as cerebrovascular diseases: they have an increased expression of the ACE2 receptor in their brain vascular and neuronal (astrocyte) cells.

The researchers are also hopeful of extending these findings beyond the vulnerable groups explored in their study. Speaking of the potential scientific and socio-economic ripple effects of their study, Dr. Koh says, “While this study focused on strokes, diabetes, and smoking, the approach followed can be applied to other groups at high risk of severe COVID-19 infection, such as the elderly and patients with chronic diseases like chronic respiratory disease or cancer. Furthermore, our results have been used as the basis for some COVID-19 prevention and quarantine guidelines, such as smoking cessation and observance of social distancing rules.”

These findings are, after all, a firmer affirmation of the fact that some groups of people are more vulnerable to the disease than others and should be protected. 

Reference

Authors                          Ji-Young Choi, Hye-Kyung Lee, Jung Hyun Park, Sun-Jung Cho, Munjin Kwon, Chulman Jo, Young Ho Koh

Title of original paper     Altered COVID-19 receptor ACE2 expression in a higher risk group for cerebrovascular disease and ischemic stroke

Journal                           Biochemical and Biophysical Research Communications

DOI                                10.1016/j.bbrc.2020.05.203

Affiliations                      Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health

About National Institute of Health in Korea

The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.

Website: http://www.nih.go.kr/eng/

About Professor Young Ho Koh

Dr. Koh Young-ho is the director of brain disease research at the National Institute of Health, Korea. His research interests include molecular neurobiology, neuroscience, and Alzheimer's disease. To date, he has 71 publications to his name.