key: cord-0800998-frl3qthc
authors: Sarantis, Panagiotis; Koustas, Evangelos; Papavassiliou, Athanasios G.; Karamouzis, Michalis V.
title: Are cystic fibrosis mutation carriers a potentially highly vulnerable group to COVID‐19?
date: 2020-10-03
journal: J Cell Mol Med
DOI: 10.1111/jcmm.15941
sha: 36421cfd142824c335de906c40eac11b13bebf0c
doc_id: 800998
cord_uid: frl3qthc

Undoubtedly, the new SARS‐CoV‐2 virus poses a grave health threat, plaguing the health and socio‐economic sectors. COVID‐19 disease must be treated quickly and effectively as soon as possible. The main axes in this direction are establishing vaccines, drugs, diagnostic tests, as well as identifying the most vulnerable groups. Probably, there is a correlation between COVID‐19 and cystic fibrosis. Our interest is focused on cystic fibrosis carriers that, due to limited tests, remain undetectable. There is an activation of the inflammatory response in the carriers, as well as in cystic fibrosis patients. First of all, a striking similarity lies between the inflammatory response in COVID‐19 and cystic fibrosis carriers. Notably, ACE‐2 plays the same role in both cases and a similar geographical distribution is observed in both diseases. In conclusion, we suggest that cystic fibrosis mutation carriers are potential members of a certain vulnerable group and the detection of such mutations in the population might be vital for the prevention of SARS‐CoV‐2 virus, and more specifically to limit its serious complications.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, located on the long arm of chromosome 7. The first clinical description of the syndrome was in 1939, and the responsible gene was successfully cloned in 1989. 1 The CFTR gene encodes an adenosine triphosphate (ATP)binding cassette (ABC) transporter of the cell membrane. The term CFTR-related disorders (CFTR-RD) describe a subgroup of patients with marked CFTR dysfunction, but they do not complete the CF diagnosis criteria. This term involves three discrete clinical entities: congenital bilateral absence of the vas deferens, acute recurrent or chronic pancreatitis and disseminated bronchiectasis. 2 One of the most common mutations in the CFTR gene is functional significance 9 (ΔF508 or F508del) and is present in approximately 85% of CF patients worldwide. F508del caused by a phenylalanine deletion at position 508 on chromosome 7, and it accounts for over two-thirds of all detected mutations in northern Caucasian populations. 3 

It is widely known that in the presence of ΔF508-CFTR mutation, NFκB appears to be constitutively activated. This leads to IL-8 depended chronic neutrophilic lung disease. New evidence supports the hypothesis that the imbalance of inflammation response appears to be an intrinsic component of the CF and airway, and lung inflammation may occur in absence or infection. In addition, lung epithelial cells, with mtCFTR, secrete pro-inflammatory cytokines and enhance the activation of NFκB. 4 The mechanism by which mt CFTR leads to abnormalities of the NFκB inflammation pathway is still ambiguous. TRADD (tumour necrosis factor receptor type 1-associated DEATH domain protein) is the main c signalling intermediate component between TNF-α and NF-κB. 5 In CF cases, TLR-2,3 and 4 appear to be activated, and therefore, an acute innate immune response is triggered through NF-κB-depended transcription of inflammatory cytokines genes. 6 Therefore, NF-κB translocates to the nucleus and triggers the transcription of pro-inflammatory genes TNF-α, IL-6, IL-8 and arachidonic acid metabolites. 7 The cytokine storms in CF patients and carriers of mt CFR are presented in Figure 1 .

Cystic fibrosis carriers are at an elevated risk of developing a broad scale of conditions related to CF in several organs. Carriers have ∼50% as much CFTR anion channel activity as the healthy people have.

Unusually acidic airway surface liquid could drive lung disease in CF patients and may elucidate the important risk of lung disease for carriers. Further studies of epithelial Cl − and HCO3 − secretion, particularly under stimulated conditions, may yield a better perceptive of how the reduced CFTR may affect or not to the disease in many organs. 8 Because of the high frequency of CF carriers (about 1 in 25 people of Northern Europe), the probability of respiratory infections and related antibiotic use attributable to the CF carriers could be substantial. Furthermore, the heterozygote state could contribute to persistent respiratory infections. In addition, CF carriers have an elevated risk of asthma than non-carriers. 9

The vigorous study of SARS-CoV-2 infection reveals high plasma levels of a plethora of pro-inflammatory cytokines, such as MCP,

The sensitivity of cystic fibrosis transmembrane regulator (CFTR) carriers to COVID-19 inflammatory response. The absence of functional CFTR on the surface of the airway cells mediates the inflammatory response in CF that initiates a chronic pro-inflammatory response through NFκB (A). In the presence of ΔF508-CFTR on the cell surface of CF heterozygotes is a critical mediator of this hyperinflammatory immune response. Furthermore, in the presence of misfolded CFTR protein may also trigger the NFκB inflammation signalling pathway (B). The endocytosis of the ACE-2 receptor after COVID-19 binding leads to the accumulation of Angiotensin II and, therefore, respiratory distress and lung injuries through NF-kB signalling (C). Consequently, heterozygotes of CFTR are more sensitive to cytokine storms mediated by NF-kB, and the severity of SARS-CoV-2 is higher on this population IL1-β, TNF-α, VEGF-A and IFNγ, suggesting the pathogenic role of cytokine storms mediated by overproduction of pro-inflammatory cytokines related to damage and disease severity in COVID-19 patients. 10 Besides, high levels of IL-1 and IL-6 are noticed in response to COVID-19, highlighting that there might be a correlation between cytokine release syndrome and COVID-19 infection. 11 Therefore, the unabated overproduction of pro-inflammatory cytokines (described as a cytokine storm) leads to an increased risk of vascular hyperpermeability, multiorgan failure and eventually death. 12 Several studies have revealed viral structural and non-structural proteins that antagonize interferon responses in various steps, including by inhibiting PRR recognition of viral RNA, by preventing PRR axis through TBK1/inhibitor of nuclear factor-κB kinase subunit-ε (IKKε), TRAF3 and IRF3, by inhibiting downstream interferon signalling through STAT1 and by initiating host mRNA degradation and inhibiting the translation of host protein. Antagonism and alteration of interferon response promote viral replication, which leads to increased release of pyroptosis products and, therefore, further induces inflammatory response. 11 

ACE-2 (angiotensin-converting enzyme 2) is an ectoenzyme that converts angiotensin II to angiotensin (1-7). The pathogenesis of lung fibrosis involves the down-regulation of ACE-2, leading to lung collagen deposition. Additionally, ACE-2 enzymatic activity is rigorously decreased in both human and experimental animals, lung fibrosis. 

invade the host cell. The SARS-CoV-2 S-protein is bearing mutations that increase its affinity to human ACE-2 by ~10-15-fold compared to SARS-CoV S-protein, making it exceedingly infectious. Once the SARS-CoV-2 virus binds to ACE-2, it prevents ACE-2 from performing its normal function to regulate ANG II signalling. Consequently, ACE-2 action is repressed and makes more ANG II available to injure tissues. 14 The role of ACE-2 in cytokine storm mediated by COVID-19 binding is presented in Figure 1 . 

In the present article, we first describe the typical inflammatory response course and the cytokine cataract between COVID-19 and cystic fibrosis (patients and carriers). Also, it is seen that there is the direct involvement of ACE-2 in the pathophysiology of COVID-19 and cystic fibrosis. Finally, there is an almost identical distribution of cystic fibrosis patients and deaths by COVID-19 worldwide. These three characteristics are likely to support a correlation between SARS-CoV-2 cases and the increased sensitivity of cystic fibrosis mutation carriers.

In conclusion, we suggest the investigation, especially in the most severe COVID-19 cases, if there is a correlation with cystic fibrosis mutation carriers. If this is proven true, more diagnostic molecular F I G U R E 2 Geographical distribution. The geographical distribution of total deaths caused by COVID-19 (Map from WHO, on 11 July). In both diseases, Central and Western Europe, as well as North America, have the most significant impact and generally follow the same geographical distribution tests for detecting CF mutation carriers in the population will be needed. Such a possible association could create a significant protection net for cystic fibrosis mutation carriers and be vital for the prevention of the SARS-CoV-2 virus and its serious complications.

The authors declare no potential conflicts of interest. 

Identification of the cystic fibrosis gene: genetic analysis

Recommendations for the classification of diseases as CFTR-related disorders

Spatial patterns of cystic fibrosis mutation spectra in European populations

The NF-kappaB signaling in cystic fibrosis lung disease: pathophysiology and therapeutic potential

CFTR controls the activity of NF-κB by enhancing the degradation of TRADD

Toll-like receptor 4 is not targeted to the lysosome in cystic fibrosis airway epithelial cells

Expression of the nuclear factor-κB inhibitor A20 is altered in the cystic fibrosis epithelium

Relationships among CFTR expression, HCO3-secretion, and host defense may inform geneand cell-based cystic fibrosis therapies

CFTR heterozygotes are at increased risk of respiratory infections: a population-based study

The trinity of COVID-19: immunity, inflammation and intervention

Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells

COVID-19 cytokine storm: the interplay between inflammation and coagulation

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis

Hypertension prevalence in human coronavirus disease: the role of ACE system in infection spread and severity

The future of cystic fibrosis care: a global perspective