COVID-19 Research: John Hopkins Study Shows That Obesity Upregulates ACE2 And TMPRSS2 Expression
: A new study by researchers from John Hopkins involving young obese mice has found that obesity typically leads to upregulation of ACE2 receptor expression especially in the lungs and trachea, increasing the risk factor for SARS-CoV-2 infection and severity.
In the study, the researchers demonstrated that:
expression is elevated in the lung and trachea of diet-induced obese male mice and reduced in the esophagus of obese female mice relative to lean controls;
expression is increased in the trachea of obese male mice but reduced in the lung and elevated in the trachea of obese female mice relative to lean controls;
-c) in chow-fed lean mice, females have higher expression of Ace2
in the lung and esophagus as well as higher Tmprss2
expression in the lung but lower expression in the trachea compared to males;
-d) in diet-induced obese mice, males have higher expression of Ace2
in the trachea and higher expression of Tmprss2
in the lung compared to females, whereas females have higher expression of Tmprss2
in the trachea relative to males.
The study findings indicate diet- and sex-dependent modulation of ACE2 and Tmprss2 expression in the lower respiratory tract and esophagus.
The study findings were published on a preprint server but are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.10.13.337907v1
In the past, how exactly obesity affects disease progression was constantly contested, with studies suggesting changed lung function due to obesity, vascular health, or a change in the immune system.
It is already known that 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.
Also since the virus mainly affects the respiratory system, it is believed that the virus's main route is via the respiratory tract.
The study team initially hypothesized that obesity changes ACE2 and TMPRSS2 expression in the lower respiratory tract, which could add to the risk of developing COVID-19. Furthermore, the team also studied both male and female mice to understand the differences in COVID-19 severity and mortality between sexes.
The study team 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.
The team harvested th
e 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.
Significantly 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.
Also there was no difference in the ACE2 expression in the esophagus of obese and lean mice.
The trachea connects the upper airway (nose and throat) to the lung and thus represents an additional high virus-to-tissue contact zone. In this organ, Ace2 expression was also significantly higher in obese male mice relative to lean male controls or to obese female mice. Together, these observations may potentially account, at least in part, for the association of obesity with SARSCoV-2 infection and COVID-19 severity, as well as the male-biased mortality rate.
Importantly 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.
Interestingly 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.
Also 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.
It was also observed that 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.
It must be noted that to date, 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 detailed 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461480/
Hence 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.
It has been suggested that other cellular proteases (e.g., furin and cathepsin B/L) may potentially be used by SARS-CoV-2 to enter TMPRSS2-negative cells. Thus, elevated Ace2 viral receptor expression in the trachea of obese male mice, despite lower expression of TMPRSS2, may still favor viral entry if other cellular proteases can substitute for TMPRSS2.
The study team does 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.
In addition, 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.
In summary, the study provides valuable insights into dynamic expression of the SARS-CoV-2 cell entry receptor and an important associated protease in the context of obesity and sex. This information will help inform the ongoing understanding of COVID-19 pathophysiology.
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