Researchers studying young obese mice found that expression of ACE2, a receptor in host cells that binds to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is higher in the lungs and trachea of obese mice. The finding could partly explain why obesity is a high-risk factor for COVID-19.
With the continued spread of COVID-19 caused by the SARS-CoV-2 virus, several studies have highlighted the risk factors for disease severity and death. One of these factors is obesity.
How exactly obesity affects disease progression is still contested, with studies suggesting changed lung function due to obesity, vascular health, or a change in the immune system.
The SARS-CoV-2 virus infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) on the host cell’s surface. This is believed to be facilitated by the expression of the serine protease TMPRSS2 by the host cell, which cleaves the spike protein for entry. ACE2 and TMPRSS2 are both expressed in different types of cells in humans, such as the heart, lungs, kidneys, and the liver.
Since the virus mainly affects the respiratory system, it is believed that the virus’s main route is via the respiratory tract.
In a new study published on the preprint server bioRxiv* in October 2020, researchers from Johns Hopkins University School of Medicine hypothesized that obesity changes ACE2 and TMPRSS2 expression in the lower respiratory tract, which could add to the risk of developing COVID-19. Furthermore, they also studied both male and female mice to understand the differences in COVID-19 severity and mortality between sexes.
Obese mice show elevated ACE2 expression
The researchers tested their hypothesis on obese mice. They fed male and female mice a high-fat diet, with 60% of their calories derived from fat. After five months of this diet, the mice gained a lot of weight and fat.
They harvested the lung, trachea, and esophagus from euthanized mice and isolated RNA from these organs. Using real-time polymerase chain reaction (RT-PCR), they tested the levels of ACE2 and TMPRSS2.
Real-time PCR testing showed higher expression of ACE2 in the lungs and trachea of the obese male mice compared to that of lean mice, which served as the control. In contrast, TMPRSS2 was reduced in the trachea of obese mice. There was no difference in the ACE2 expression in the esophagus of obese and lean mice.
However, in the obese female mice, there was reduced ACE2 expression in the obese mice compared to that of the lean mice. TMPRSS2 expression was significantly reduced in the lungs and increased in the trachea of obese females.
There were also differences in the expression in male and female mice. In the lean mice, females had higher ACE2 expression in the lungs and esophagus than males. Females had higher TMPRSS2 expression in the lungs and lower expression in the trachea compared to lean males. There was no difference in TMPRSS2 expression in the esophagus of the lean mice.
In obese mice, males had higher expression of ACE2 in the trachea and TMPRSS2 in the lungs than females, whereas females had higher TMPRSS2 expression in the trachea.
Altered ACE2 expression could increase COVID-19 risk
COVID-19 patients experiencing severe symptoms are seen to have higher viral loads in the respiratory tract, and the levels of ACE2 and TMPRSS2 are thought to play a role in the viral loads.
A meta-analysis of 75 published studies from more than ten countries in Asia, Europe, and the Americas found that obesity was one of the highest risk factors for COVID-19 diagnosis, hospitalization, and a 48% higher risk for death. Men seem to have about 2.5% higher mortality than women.
The higher ACE2 expression in obese male mice trachea compared to lean mice and females could explain the higher risk for obese males. Although obese males have lower TMPRSS2 expression, the virus may use other cellular proteases to enter the host cell.
The authors do note some limitations of the study. They quantified the ACE2 and TMPRSS2 expression from bulk RNA from whole tissues. So, they did not identify the source cells for their expression.
Furthermore, the mice they used in the study were only six months old, which would correspond to young humans. However, it has been seen that death from COVID-19 is significantly higher in older people. Hence, further investigations on older mice are required to test how age affects the expression of ACE2 and TMPRSS2.