Goblet cells are prime target for SARS-CoV-2, study finds

As the coronavirus disease 2019 (COVID-19) pandemic continues to rage over much of the world, researchers are striving to understand how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes manifestations of the disease.

A recent paper published on the preprint journal bioRxiv* reports 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 virus and plays a vital role in promoting viral replication in this tissue.

Study: Goblet Cell Hyperplasia Increases SARS-CoV-2 Infection in COPD. Image of Goblet cells in the ciliated respiratory epithelium of the trachea, with their mucus stained in violet color. Elastic fibers located under the epithelium are also stained. Light microscope picture. Image Credit: Jose Luis Calvo / Shutterstock
Study: Goblet Cell Hyperplasia Increases SARS-CoV-2 Infection in COPD. Image of Goblet cells in the ciliated respiratory epithelium of the trachea, with their mucus stained in violet color. Elastic fibers located under the epithelium are also stained. Light microscope picture. Image Credit: Jose Luis Calvo / Shutterstock

Angiotensin-converting enzyme 2 expression

SARS-CoV-2 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.

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. 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.

The importance of goblet cells

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.

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.

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).

Preferential infection of goblet cells

Many earlier studies indicate that the virus 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 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.

Syncytia and cell sloughing

The researchers 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, was reproduced here in infected cells, both in healthy and COPD epithelium.

Autopsies 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.

Intensification of infection

The researchers 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.

Implications

The researchers conclude, “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.”

These 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. This study 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.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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