COVID-19 meets cystic fibrosis, for better or for 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

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 secretion of chloride and bicarbonate, as well as dysregulation of epithelial sodium channels (ENaC). These changes result in poor mucociliary clearance, a reduction in the liquid surface area of the respiratory tract, and an exaggerated pro-inflammatory response, in part caused by the infection.

In this short article, we explore the overlap in the pathophysiology of CF and COVID-19 infection and look at 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 a potentially fatal acute respiratory distress syndrome. Cystic fibrosis (CF) patients also manifest cytokine dysfunction and hyper-inflammation that overlaps with 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, health services have responded with protection or cocooning policies. 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 due to respiratory syncytial virus (RSV) infection are lower than expected in children with CF. In a previous RSV epidemic, 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 ventilation capacity for children, not a single child with CF was bothered by the virus (AM personal observations over two decades). The few CF patients in the RSV cohort could be explained by the recent proposal that RSV requires an intact autophagic pathway to replicate, as well as by the discovery of the dysregulation of autophagy in CF cells. There is some speculation that the induction of autophagy, which is increased in CF, may counteract COVID-19 infection, although data remain limited.

Conversely, there are solid theoretical reasons why CF could be expected to heighten rather than mitigate the impact of COVID-19 infection. CFTR mutations disrupt cellular metabolism and exaggerate the pulmonary and systemic effects of COVID-19 infection.
CFTR mutations disrupt cellular metabolism and exaggerate pulmonary inflammatory responses, with dysregulation of the assembly of the NLRP3 inflammasome multiprotein complex, which processes pro-inflammatory cytokines. The SARS-CoV-2 virus enters host cells using a spike protein to bind to the cell membrane protein, angiotensin-converting enzyme 2 (ACE2). Entry into the cell, via ACE2, is facilitated by the enzyme furin, which makes these two factors essential actors in infection. ACE2 has a site potentially activated by furin, which converts and activates viral surface glycoproteins and also regulates ENaC. The activation of furin, which is increased in CF, as well as the cellular damage induced by viroporins, could be the cause of an 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 some VOCs has previously been 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 infectious bronchitis virus (IBV) S protein results in higher pathogenicity, pronounced neuronal symptoms, and neurotropism in infected chickens.
It is therefore entirely 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 believed to mimic the proteolytic activation of ENaC, an ion channel that is significantly upregulated in CF, where it causes inflammation and is essential for airway surface liquid homeostasis.

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 a hundred cases of COVID-19 infection in people with CF, about 90% of whom had relatively few symptoms and complications. While the numbers and results may simply reflect effective protection, it is very likely that some regions, such as New York State and northern Italy, would have reported significant numbers of FK-COVID-19 deaths if patients had been highly 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 come from cellular processes affected by CF related to viral treatment, including autophagy, mitophagy, mitophagy, endosomal function, and cellular metabolism, all of which can be co-opted by COVID-19 for viral replication.

We hypothesize that CFTR modulator treatment could also provide an additional benefit to patients with severe respiratory problems due to COVID-19 infection.For example, CFTR modulatory therapy given to people with CF helps restore cellular function, increases airway hydration, increases airway hydration, reduces oxidative stress, and regulates NLRP3 inflammasome activation. 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 an in vitro CFTR potentiator. Carriers of the Phe508del mutation (by far the most common), found in over 70% of patients, were also identified as having an increased risk of developing chronic bronchitis and bronchiectasis.

The role of CFTR in COVID-19 needs to be clarified in patients without CF. In an influenza model, the CFTR corrector, lumacaftor, was shown to be able to reverse in vitro the negative regulation of CFTR and ENaC following a viral infection and to restore airway surface fluid.
CFTR and ENaC have both been proposed as theoretical cleavage sites for the coronavirus proteinase enzyme 3CLpro, which controls viral replication. Transmembrane serine protease 2 (TMPRSS2), which may facilitate the entry of the virus into the target host cell, also reduces ENaC activity in the airway epithelium. The results obtained in people with CF can 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 in antiviral therapy. We suggest that clinical trials of modern CF medications 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 CF registry managers to collect such case-control data to inform future studies.

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