COVID-19 Meets Cystic Fibrosis, For Better Or Worse?

Sources : COVID-19 meets Cystic Fibrosis: for better or worse?
Genes Immun 21, 260–262 (2020).
https://doi.org/10.1038/s41435-020-0103-y

Full article and illustrations available in the SVB 2020

Summary
Cystic fibrosis (CF) is one of the most common autosomal recessive life-limiting conditions in Caucasians. The resulting defect in the transmembrane conductance regulatory protein (CFTR) results in defective chloride and bicarbonate secretion, as well as epithelial sodium channel (ENaC) dysregulation. These changes lead to poor mucociliary clearance, reduced airway surface fluid and an exaggerated pro-inflammatory response, partly caused by infection.


In this brief article, we explore the overlap between the pathophysiology of CF and COVID-19 infection and examine how understanding the interaction between these two diseases can inform future treatments.
Infection with COVID-19 (SARS-CoV-2) triggers a cytokine storm, sepsis and life-threatening acute respiratory distress syndrome. Patients with cystic fibrosis (CF) also exhibit cytokine dysfunction and hyper-inflammation that overlaps the pathophysiology of COVID-19. Intuitively, one could conclude that CF patients infected with COVID-19 would be at high risk of developing severe symptoms of the disease. As a result, the health services reacted with policies of protection or cocooning. A randomized Mendelian experiment is indeed underway, in real time, in which patients with two mutant copies of the CFTR gene are exposed to a new virus. While respiratory viruses, such as rhinoviruses and influenza, are associated with increased pulmonary exacerbations, morbidity and mortality from respiratory syncytial virus (RSV) infection is lower than expected in children with FK. In a previous RSV outbreak, relatively few CF patients were found to become seriously ill.
For example, at a time when so many babies were wasting away to the point that a regional intensive care unit exceeded its capacity to ventilate children, not a single child with CF was bothered by the virus (personal observations AM over two decades). The small number of CF patients in the RSV cohort could be explained by the recent proposition that RSV needs an intact autophagic pathway to replicate, as well as the discovery of autophagy deregulation in cells. FK. There is some speculation that the induction of autophagy, which is increased in CF, could thwart COVID-19 infection, although data remains limited.


Conversely, there are sound theoretical reasons why one might expect CF to increase rather than lessen the impact of COVID-19 infection. CFTR mutations disrupt cell metabolism and exaggerate the pulmonary and systemic effects of COVID-19 infection.
CFTR mutations disrupt cell metabolism and exaggerate pulmonary inflammatory responses, with deregulation of the assembly of the multiprotein inflammasome complex NLRP3 which processes pro-inflammatory cytokines. The SARS-CoV-2 virus enters host cells using a spike protein to bind to the cell membrane protein, the angiotensin-converting enzyme 2 (ACE2). Entry into the cell, via ACE2, is facilitated by the enzyme furin, which makes these two factors essential players in infection. ACE2 has a potentially furin-activated site, which converts and activates viral surface glycoproteins and also regulates ENaC. Activation of furin, which is increased in CF, as well as cell damage induced by viroporins, may be responsible for upregulation of NLRP3 and inflammation. Many of us have reported that the NLRP3 inflammasome is abnormal in CF cells.

The role of furin in viral pathogenesis has recently been examined and the authors state that “the pathogenesis of certain VOCs has been previously linked to the presence of a furin-like cleavage site in the S protein sequence”. For example, the insertion of a similar cleavage site into the S protein of infectious bronchitis virus (IBV) results in higher pathogenicity, pronounced neural symptoms and neurotropism in infected chickens.
It is therefore highly plausible that furin activity is a key factor in COVID-19 infections and it will be important to test furin inhibitors as therapeutic agents in future studies. The SARS-CoV-2 virus is said to mimic the proteolytic activation of ENaC, an ion channel that is significantly upregulated in CF, where it causes inflammation and is essential for fluid surface homeostasis. airway.


There is still little data on the response of CF to COVID-19 infection, although preliminary information suggests that the course of the disease may be milder than expected. Globally, based on a population of around 100,000 patients, there have been over 100 cases of COVID-19 infection in people with CF, of which around 90% had relatively few symptoms and complications. While the numbers and results may simply reflect effective protection, it is very likely that some areas, such as New York State and northern Italy, have reported significant numbers of FK-COVID-19 deaths. if the patients had been very sensitive to it.
If further clinical experiences indicate that the course of COVID-19 infection in patients with CF is milder than expected, then it could be proposed that the relative protective effect associated with CF may be due to the processes cells affected by CF linked to viral processing, including autophagy, mitophagy, endosomal function, and cell metabolism, all of which can be co-opted by COVID-19 for viral replication.

We hypothesize that CFTR modulator therapy may also confer an additional benefit to patients with severe respiratory problems due to COVID-19 infection. For example, CFTR modulator therapy given to people with CF helps restore cellular function, increases hydration of the respiratory tract, reduces oxidative stress and regulates the activation of the NLRP3 inflammasome. The influence of CFTR in respiratory diseases other than CF is intriguing and relatively poorly understood. Recent reports have demonstrated that acquired CFTR dysfunction occurs in smokers, and that the acute reduction in CFTR function due to cigarette smoke extract may be reversible by a potentiator of CFTR in vitro. Carriers of the Phe508del mutation (by far the most common), found in over 70% of patients, have also been identified as having an increased risk of developing chronic bronchitis and bronchiectasis.

The role of CFTR in COVID-19 should be clarified in patients without CF. In an influenza model, the CFTR corrector, lumacaftor, was shown to be able to reverse the downregulation of CFTR and ENaC following viral infection in vitro and restore surface fluid to the pathways. aerial.
Both CFTR and ENaC have been proposed as theoretical cleavage sites for the coronavirus proteinase 3CLpro enzyme, which controls viral replication. The transmembrane serine protease 2 (TMPRSS2), which may facilitate the entry of the virus into the target host cell, also reduces the activity of ENaC in the airway epithelium. Findings in people with CF may provide clues about how these factors interact in the real world.


The clinical importance of characterizing the effects of COVID-19 infection in patients with CF and understanding the possible underlying protective effects could shed light on new targets and approaches to therapy antiviral. We suggest that clinical trials for modern CF drugs be explored in people infected with this new virus. In practice, a pragmatic trial is already underway, the outcome of which will depend on the response to COVID-19 in patients who are or are not receiving modern CF drug combinations, and we also invite all registrars to CF to collect such case-control data to inform future studies.

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Sébastien Puli
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