This rare disease group may be immune to the new crown

Recently (January 10), an article published in Nature Communications provided another idea
of possible potential solutions to the new coronavirus.
Researchers tried to clarify the relationship between cystic fibrosis and the new coronavirus, at first they thought that patients with this disease may be the same respiratory related disease to deepen the comorbidity of the new crown, but then they found that this disease that most patients do not live to be 50 years old may protect patients from new crown virus infection
.

Not only that, based on this patient population and in vitro clinical analysis, it seems that this mechanism can be used to obtain specific drugs
for the new crown.

Cystic fibrosis is the first disease in the world to be treated with AAV genes
, as described in previous articles.

Patients often do not live to be 50 years old, and the main group of patients is Ashkenazi Jews (more famous are Einstein, Oppenheimer and Goldman Sachs founder Marcus Goldman).

This patient group has created the Cystic Fibrosis Foundation, the largest single-disease foundation in the United States, and has been pouring hundreds of millions of dollars
into cystic fibrosis research.

Further reading:

Why do these rare disease drugs sell well?

Gene therapy apocalypse | the first human clinical failure of AAV in history

Pathogenesis and patient report

Cystic fibrosis occurs due to defects in the cystic fibrosis transmembrane conduction regulator (CFTR) gene, which encodes chloride and bicarbonate channels
that are widely expressed in human epithelial cells.
The expression or loss of function of CFTR in the airway epithelium may impede the transmembrane transport of water and electrolytes in the respiratory mucosal epithelium, increase the content of acid glycoprotein in mucus gland secretions, and change the characteristics of
mucus rheology.

This process is thought to be the initiation event of the pathogenesis of CF airway disease and eventually leads to severe impairment of lung function, often with chronic obstructive pulmonary disease (COPD).

Therefore, CF may be considered an adverse comorbidity in patients with novel coronary pneumonia, especially considering that other respiratory viral infections, including respiratory syncytial virus (RSV) and influenza A(H1N1), can lead to rapid deterioration of lung function and increased mortality in CF patients
.

However, reports of coronavirus infections in CF patients in Belgium, France, Spain, Germany, and Italy make this claim even more scrutinizing, as these patients usually show fairly mild symptoms
after infection.
Based on this, the European Cystic Fibrochemistry Society (ECFS) concluded that the CF patient population has a lower mortality rate associated with new coronary pneumonia than the general population
.

Why does the CF patient population seem to be insulated from the new crown?

To explain the problem seems to return to the mechanism of action of CF itself, the researchers used primary human bronchial epithelial cells (hBEC) and nasal epithelial cells (hNEC) isolated from CF patients to analyze the specific data
.

They were surprised to find that ACE2 receptors, one of the main pathways of new coronavirus infection, were expressed down-regulated
in two epithelial cells of CF compared to normal human epithelial cells.
(as shown in the figure below)

Based on this, the researchers speculate that the downregulation of the gene CFTR may have induced the inhibition
of the ACE2 receptor.
To test this conjecture, the researchers verified the expression levels of ACE2 in bronchial epithelial cell lines at different CFTR expression levels, and found that CFTR expression was positively correlated
with the ACE2 protein levels in bronchial epithelial cells.

Immunofluorescence detection of cells confirmed that the CFTR gene showed co-localization with ACE2 receptors to bronchial epithelial cells
.

In addition, CRS is an important factor in the death of many new crown patients, the novel coronavirus protein will bind to the ACE2 receptor expressed on the surface of the host cell, stimulate the release of IL-6 and other pro-inflammatory mediators, thereby forming CRS (cytokine storm) However, for CF patients, CF may hinder the airway epithelial CRS
triggered by the stimulation of the new coronavirus protein.

CFTR inhibitors

Since the correlation between CFTR and ACE2 has been confirmed, the theory is applied to practice, and since down-regulation of CFTR may inhibit ACE2 expression, can the use of CFTR inhibitors hinder the infection and replication of the new coronavirus?

The researchers specifically downregulated CFTR synthesis through the CFTR inhibitor CFTR(inh)172 and the use of Calu-3 cells' miRNA-based methods to observe whether the loss or downregulation of CFTR in vitro cell lines could inhibit the entry and replication
of the new coronavirus.

It was found that after the treatment of these two methods, the loss of CFTR expression and function inhibited the entry and replication
of the novel coronavirus.
(as shown in the figure below)

Summary

Overall, this study sheds light on some of the links and findings between cystic fibrosis and COVID, in addition to CFTR and other possible chloride channels that could serve as molecular targets for the development of alternative anti-COVID therapies
.

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