COVID-19 News: Chicago Study Finds That Hypercapnia And Cigarette Smoke Increases ACE2 Expression And SARS-CoV-2 Entry In Bronchial Epithelial Cells

COVID-19 News: The COVID-19 pandemic has significantly impacted global health and well-being, with certain populations facing an increased risk of severe illness and death when infected with the SARS-CoV-2 virus. Among these vulnerable groups are individuals with pre-existing conditions, such as chronic lung diseases, obesity, and smokers. Recent research conducted at Northwestern University in Chicago, USA, and Jesse Brown Veterans Affairs Medical Center in Chicago, has unveiled a critical connection between hypercapnia (elevated carbon dioxide levels in the blood and tissue) and increased ACE2 expression in bronchial epithelial cells. This discovery sheds light on a potential mechanism that contributes to the poor clinical outcomes in COVID-19 patients with advanced lung disease, hypercapnia, and those who smoke. Additionally, the study suggests that cholesterol-lowering therapies, particularly statins, may offer benefits to individuals with hypercapnia when exposed to or infected with SARS-CoV-2.


                                                                                  Graphical Abstract

Understanding Hypercapnia
Hypercapnia, also known as hypercarbia, is a condition characterized by elevated levels of carbon dioxide (CO2) in the bloodstream. CO2 is a metabolic waste product that the body expels through exhalation. When the body's mechanisms for regulating CO2 levels become compromised, hypercapnia can occur, leading to an accumulation of CO2 in the blood and tissue. This condition can have detrimental effects on the body's overall health, and the recent study investigates its role in influencing the severity of COVID-19.
 
Increased Risk for Vulnerable Populations
Individuals with pre-existing health conditions, such as chronic obstructive pulmonary diseases (COPD), and those who smoke cigarettes are at a heightened risk of experiencing severe complications when infected with SARS-CoV-2. This research focuses on the role of the angiotensin-converting enzyme 2 (ACE2) in the infection process. ACE2 serves as the receptor for the SARS-CoV-2 spike protein, enabling the virus to enter and infect host cells. Previous studies have shown that ACE2 expression is heightened in the bronchial epithelium of individuals with comorbidities linked to severe COVID-19, suggesting that the increased ACE2 expression may enhance SARS-CoV-2 infection within the airways.
 
The Impact of Hypercapnia on ACE2 Expression
The study demonstrates that hypercapnia elevates ACE2 protein expression in murine airway epithelium, human bronchial epithelial cells, and VERO cells. These findings suggest that hypercapnia increases the availability of ACE2 receptors, thereby facilitating greater viral entry into bronchial epithelial cells. This observation aligns with single-cell RNA-sequencing data, which correlates ACE2 expression levels with the suscept ibility to SARS-CoV-2 infection. Furthermore, higher ACE2 transcript levels have been linked to increased viral loads in COVID-19 patients.
 
Hypercapnia's Effect on Pseudo-SARS-CoV-2 Entry
To investigate the influence of hypercapnia on SARS-CoV-2 entry, the research examined pseudo-SARS-CoV-2 (p-SARS-CoV-2) infection in epithelial cells. The results showed that culture under elevated CO2 conditions increased the percentage of cells that tested positive for p-SARS-CoV-2, indicating an enhancement of viral entry. This effect was consistent with the observed increase in ACE2 protein expression and demonstrated the reversible nature of the changes when cells were returned to normocapnic conditions.
 
Cholesterol and Lipid Rafts: Key Players
The study delves into the relationship between hypercapnia and cholesterol in bronchial epithelial cells. Notably, factors that increase the cholesterol content of lipid rafts and lipid droplets, crucial platforms for viral entry and assembly, have been found to enhance SARS-CoV-2 infection. These observations raise questions about the role of cholesterol in viral entry and infection. The study also identifies the role of the transcription factor sterol-regulatory element binding protein 2 (SREBP2), which regulates cholesterol synthesis and transport genes. Hypercapnia was found to activate SREBP2, leading to an increase in cholesterol synthesis and a decrease in cholesterol efflux through ABC transporters. In essence, this creates a favorable environment for SARS-CoV-2 to enter and infect host cells.
 
Cholesterol-Lowering Therapies as a Potential Solution
In response to the findings, the study investigates the potential of cholesterol-lowering therapies to mitigate the effects of hypercapnia on ACE2 expression and SARS-CoV-2 entry. Two types of inhibitors were tested: SREBP2 inhibitors and statins. Both were effective in blocking the hypercapnia-induced increases in ACE2 expression and p-SARS-CoV-2 entry. Statins, which are commonly used to lower cholesterol levels, were particularly promising. The study found that statins like fluvastatin and rosuvastatin could be potential candidates for host-directed therapy against viral infections, given their established safety records and affordability. Several studies have also suggested that statins may provide protection against severe COVID-19, making them a valuable avenue for further research and potential therapeutic application.
 
The Impact of Cigarette Smoke Extract
The study also investigates the effects of cigarette smoke extract (CSE) on ACE2 expression, p-SARS-CoV-2 entry, and cholesterol accumulation in bronchial epithelial cells. Past studies and COVID-19 News reports had shown that active smoking is associated with increased mortality in patients with chronic hypercapnia and COVID-19, and CSE is known to increase ACE2 expression and cholesterol accumulation in respiratory tract cells. The study findings revealed that CSE independently increased ACE2 expression and p-SARS-CoV-2 entry through similar cholesterol-dependent mechanisms as hypercapnia. Furthermore, the effects of hypercapnia and CSE were found to be non-additive and non-synergistic, suggesting that both independently increased cholesterol content to a maximum capacity.
 
Statins as a Potential Solution for CSE-Induced Effects
As with hypercapnia, the study explored the potential of statins in mitigating the effects of CSE on bronchial epithelial cells. Fluvastatin and rosuvastatin were found to block the increase in cholesterol in lipid rafts stimulated by CSE. These statins also inhibited the CSE-induced increases in ACE2 expression and p-SARS-CoV-2 internalization. The results suggest that inhibiting cholesterol synthesis with statins can effectively counteract the increased cholesterol levels caused by cigarette smoke, leading to reduced ACE2 expression and reduced entry of p-SARS-CoV-2 into epithelial cells.
 
Discussion and Implications
The research has provided valuable insights into the intricate relationship between hypercapnia, cigarette smoke, and ACE2 expression in bronchial epithelial cells. The findings suggest that hypercapnia contributes to the increased ACE2 expression observed in individuals with chronic lung diseases and other comorbidities, potentially making them more susceptible to severe COVID-19. Furthermore, the reversible nature of hypercapnia-induced effects when cells return to normocapnic conditions indicates potential opportunities for intervention.
 
Cholesterol, particularly its accumulation in lipid rafts and lipid droplets, plays a critical role in facilitating the entry and infection of SARS-CoV-2 in bronchial epithelial cells. This discovery highlights the importance of targeting cholesterol as a potential therapeutic approach to mitigate the effects of hypercapnia and cigarette smoke on ACE2 expression and viral entry. Statins, which are commonly used to lower cholesterol levels, emerge as a promising avenue for host-directed therapy against viral infections and are already associated with potential benefits in preventing severe COVID-19.
 
These study findings emphasize the importance of addressing hypercapnia and smoking-related effects on bronchial epithelial cells, potentially through cholesterol-lowering therapies, to reduce the risk and severity of COVID-19 in vulnerable populations. As the world continues to grapple with the ongoing COVID-19 pandemic, this research paves the way for novel strategies to improve outcomes for individuals with pre-existing conditions and those exposed to harmful environmental factors.
 
The study findings were published in the peer reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251120/full
 
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