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Source: COVID-19 Research  Nov 17, 2020  3 years, 4 months, 1 week, 4 days, 6 hours, 47 minutes ago

COVID-19 Research: Study Shows That Goblet Cells Not Ciliated Cells Are Prime Targets For SARS-Cov-2, Also Hyperplasia Increases SARS-Cov-2 Infection In COPD

COVID-19 Research: Study Shows That Goblet Cells Not Ciliated Cells Are Prime Targets For SARS-Cov-2, Also Hyperplasia Increases SARS-Cov-2 Infection In COPD
Source: COVID-19 Research  Nov 17, 2020  3 years, 4 months, 1 week, 4 days, 6 hours, 47 minutes ago
COVID-19 Research: Scientists from University of North Dakota School of Medicine & Health Sciences, University of Nebraska Medical Center and the National Institute of Allergy and Infectious Diseases have in a new study found that goblet cells are basically the prime targets of the SARS-CoV-2 coronavirus despite the virus also being able to infect ciliated cells. The study also showed that goblet cell hyperplasia due to certain COPD issues also increases SARS-CoV-2 infection.

Chronic obstructive pulmonary disease (COPD) is one of the underlying conditions in adults of any age that place them at risk for developing severe illness associated with COVID-19. The study team established an airway epithelium model to study SARS-CoV-2 infection in healthy and COPD 19 lung cells. The team found that both the entry receptor ACE2 and the co-factor transmembrane protease TMPRSS2 are expressed at higher levels on nonciliated goblet cell, a novel target for SARS-CoV-2 infection. The team observed that SARS-CoV-2 infected goblet cells and induced syncytium formation and cell sloughing. They also found that SARS-CoV-2 replication was increased in the COPD airway epithelium likely due to COPD associated goblet cell hyperplasia.  The study results reveal goblet cells play a critical role in SARS-CoV-2 infection in the lung.
 
The study findings were published on a preprint server but are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.11.379099v1
 
The new study shows that in the airway of patients with chronic obstructive pulmonary disease (COPD), a type of airway epithelial cell called a goblet cell presents a prime target for the SARS-CoV-2 virus and plays a vital role in promoting viral replication in this tissue.
 
The SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2), along with serine protease TMPRSS2, to accomplish host cell entry and infection. The expression of these receptors determines the tissue attacked by the virus.
ACE2 is highly expressed in several human tissues, including the small intestine, testis, kidneys, heart, thyroid and fat tissue, with somewhat lower expression in the lungs, colon and liver. The lowest expression of ACE2 is in the blood, spleen and bone marrow, as well as the brain, blood vessels and muscle tissue.
 
It was found that in the lungs, which are the primary site of the disease, the type II alveolar cells are chiefly observed to express ACE2, which is also found on ciliated cells.
 
Importantly goblet cells are also found abundantly in the bronchial epithelium, and these cells primarily produce mucin. Mucin is vital to trap disease-causing germs, dust and particles, which are then cleared away by the body’s cilia.
 
It was found that goblet cells in the nose and subsegmental bronchi also show ACE2 expression at higher levels than on ciliated cells, in fact. This could explain how SARS-CoV-2 infects these cells preferentially, like the influenza A virus. This could also be why SARS-CoV-2 RNA (viral genetic material) is found in sputum, and why it can spread more rapidly between people than the earlier SARS-CoV that infected only ciliated cells. https://pubmed.ncbi.nlm.nih.gov/32246845/
 
href="https://pubmed.ncbi.nlm.nih.gov/32327758/">https://pubmed.ncbi.nlm.nih.gov/32327758/
 
https://pubmed.ncbi.nlm.nih.gov/32413319/
 
To date COPD is an important risk factor for severe COVID-19, which prompted the current study on airway epithelium using both healthy and COPD-affected lung cells. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424116/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501827/
 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html
 
Interestingly goblet cells show a rapid growth in number in COPD patients as well. The researchers thus chose to measure ACE2 expression in both normal and COPD bronchial epithelium. ACE2 and TMPRSS2 were expressed at higher levels in COPD epithelium because of the goblet cell hyperplasia (an increased proliferation of goblet cells).
 
Initial studies indicated that the SARS-CoV-2 coronavirus infects primarily ciliated cells. However, in this study, the researchers found that the virus preferentially infects goblet cells, because of their high expression of both ACE2 and TMPRSS2. The extent of infection was therefore greater in COPD epithelium compared to healthy epithelium.
 
This new finding was observed by both cytopathic assays and by immunohistochemistry assays. The latter shows that goblet cells, which produce MUC5B and MUC5AC, were infected by the virus, along with ciliated cells, but not basal cells.
 
The study team found that the infected epithelium was badly damaged by the virus, with extensive destruction of the cells and mucus secretion. The infected cells lost their connecting junctions, their cilia, and protracted nuclei. Again, the hallmark syncytia, typical of SARS-CoV-2 in the lung, were reproduced here in infected cells, both in healthy and COPD epithelium.
 
Also past autopsy studies of COVID-19 patients showed cell sloughing (or shedding). This was repeated in the current experiment, where both healthy and COPD epithelium showed sloughing following SARS-CoV-2 infection.
 
The study team found that the viral titer was higher by almost one log in COPD epithelium compared to healthy epithelium. In contrast, squamous epithelium was far more frequent in the former following viral infection. This histology is associated with the thickening of the bronchial wall, a characteristic pathological feature of fatal COVID-19. This may be due also to a change in the form of the goblet cells in this epithelium.
 
The study team concludes, “We postulate that goblet cells play a critical role in SARS-CoV-2 infection of the lung and are responsible for more severe outcome of SARS-CoV-2 infection in COPD patients.”
 
The study findings suggest that the larger number of goblet cells in the COPD epithelium makes it easier for the virus to replicate, producing more severe disease. The study revealed SARS-CoV-2 infection of goblet cells leading to virus-induced syncytium formation and cell sloughing in the airway epithelium. The team found that SARS-CoV-2 replicates better COPD airway epithelium likely due to COPD associated goblet cell hyperplasia. Thus, they postulate that goblet cells play a critical role in SARS-CoV-2 infection of the lung and are responsible for more severe outcome of SARS-CoV-2 infection in COPD patients.
 
The research findings may also explain, in part at least, why the human-to-human spread of the SARS-CoV-2 is so much greater than that of the earlier SARS-CoV, even though both share common receptors. The difference may be in the novel furin cleavage site in the former.
 
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