Do you remember The Neverending Story? Written by the German author Michael Ende – Die unendliche Geschichte
I loved it and it scared the shit out of me. You have the small boy Bastian mourning the loss of his mother – very heavy. Then he encounters the bullies while walking to school. He runs into a bookstore, slams the door with the tiny bell above alerts the storekeeper of this entrance. He hovers over schools of books and is entranced by The Neverending Story.
Then he decides to steal it and runs out and runs into the school’s attic and begins to read. I found it strange he chose the school’s attic – luminous and layered darkness, the wind and the small candle that had the potential to create a huge fire. I guess a place of great hiding.
You know as a reader or a viewer that it’s going to take some time and heavy lifting to brighten this story. One element of the brightness throughout the story is the flying animal Falkor that sometimes reminds me of my dog, Chester.
And you can feel the energy is going to bust open but you have to stick with it – through the crazy tower people, and rock man, and that horrible creature in the fog, Gmork, while Atreyu had to fight off sitting upon his beautiful horse. That was so scary.
All the while, the Empress is in a constant state of shock and bewilderment, tears plump waiting for the moment for the little human boy, Bastian, to say her name – just as The Nothing is going to take over. Remember The Nothing? The cataclysmic eruption of the earth meeting the sun.
But, then Bastian gives her a new name and he is flying through Fantasia on Falkor and then through the city streets chasing the bullies until they jump into the garbage bin.
It’s a great story.
I started this blog with a CF-related COVID article in mind. While reading, I noticed there were words I needed to refamiliarize myself with and look-up. There are many words in this world. And if I don’t look them up, they evaporate into The Nothing.
To bring them out of The Nothing, we use this handy dandy thing called the dictionary.
I am going to copy and paste this article and then provide the link below. I can input things in it to make sense if need be.
I want to say – science is stellar. The researchers are holding COVID to its core. Here is a blip from the NIH, to remind us that pretty much the only reason we may get to a possible vaccine sooner rather than later is because of the history.
“NIAID COVID-19 research efforts build on earlier research on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which also are caused by coronaviruses. MERS is a viral respiratory disease that was first reported in Saudi Arabia in September 2012 and has since spread to 27 countries, according to the World Health Organization. Some people infected with MERS coronavirus (MERS-CoV) develop severe acute respiratory illness, including fever, cough, and shortness of breath.
Only two people in the United States have tested positive for MERS-CoV, both of whom recovered. They were healthcare providers who lived in Saudi Arabia, where they likely were infected before traveling to the U.S., according to the CDC.
Infection with SARS coronavirus (SARS-CoV) can cause a severe viral respiratory illness. SARS was first reported in Asia in February 2003, though cases subsequently were tracked to November 2002. SARS quickly spread to 26 countries before being contained after about four months. More than 8,000 people fell ill from SARS and 774 died. Since 2004, there have been no reported SARS cases.”
Here is the CF-related article, “COVID-19 meets Cystic fibrosis, by Peckham, D., McDermott.
If I lose you, I understand. It is deep science, which I will try to put in a more familiar context as well as put in bold important points. This isn’t the entire article, the link posted below.
“Abstract
Cystic fibrosis (CF) is one of the most common autosomal (a chromosome that is not a sex chromosome) recessive life-limiting conditions affecting Caucasians. The resulting defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) results in defective chloride and bicarbonate secretion, as well as dysregulation of epithelial sodium channels (ENaC).”
CFTR – is a membrane protein and chloride channel in vertebrates that is encoded by the CF gene, or CFTR gene.
“These changes bring about defective mucociliary (mucus) clearance, reduced airway surface liquid, and an exaggerated pro-inflammatory response-driven, in part, by infection. In this short article, we explore the overlap in the pathophysiology (disease + normal functions of living organisms) of CF and COVID-19 infection and discuss how understanding the interaction between both diseases may shed light on future treatments.
COVID-19 (SARS-CoV-2) infection triggers a cytokine storm (interferon, interleukin, and growth factors secreted by your immune system to fight COVID), sepsis, and life-threatening acute respiratory distress syndrome [1]. Patients with cystic fibrosis (CF) also manifest cytokine dysfunction and hyper-inflammation that overlaps with the pathophysiology of COVID-19 [2,3,4].
Intuitively, it might be concluded that CF patients infected with COVID-19 would be at high risk of serious illness. As a result, health services have responded with shielding or cocooning policies. Thus, a Mendelian (theory of heredity) randomized experiment is effectively underway, in real-time, whereby patients with two mutant copies of the CFTR gene are being exposed to a new virus.
While respiratory viruses, such as rhinoviruses (common cold) and influenza, are associated with increased pulmonary exacerbations [5, 6], the morbidity and mortality from respiratory syncytial virus (RSV) infection is lower than expected in children with CF [7]. In a past epidemic of RSV, it was noted that relatively few patients with CF became severely ill.
For example, at a time when so many babies became ill that a regional intensive care unit exceeded its ventilator capacity for sick children, not a single CF-affected child became ill (AM personal observations over two decades). This paucity of CF patients in the RSV cohort (grouping) might be explained by the recent proposal that RSV may need an intact autophagic pathway (body’s way of cleaning out damaged cells) for replication [8], allied to the finding that autophagy is dysregulated in CF cells [9]. There is some speculation that inducing autophagy, which is increased in CF, may counteract COVID-19 infection, although data remain limited [10].
Conversely, there are sound theoretical reasons why CF might be expected to accentuate rather than mitigate the impact of COVID-19 infection.”
To clarify, because this sentence above strikes me:
Accentuate – make more noticeable or prominent.
Mitigate – make less severe, serious, or painful.
” CF or CFTR mutations: disrupt cellular metabolism and exaggerate both lung and systemic inflammatory responses, with dysregulation of assembly of the multiprotein NLRP3 inflammasome complex that processes pro-inflammatory cytokines [2, 3] (Fig. 1).”
Or, this from researchgate.org:
“The SARS-CoV-2 virus enters host cells by using a spike protein to bind to the cell membrane protein, angiotensin-converting enzyme 2 (ACE2) [11, 12].
Cellular entry, via ACE2, is facilitated by the furin enzyme, making both critical players in infection. ACE2 has a site that is potentially activated by furin, which converts and activates viral surface glycoproteins and also regulates ENac [13].
Activation of furin, which is increased in CF [14, 15], together with the cellular damage induced by viroporins, might be expected to upregulate NLRP3 and cause inflammation [16]. We, and others, have reported that NLRP3 inflammasome is abnormal in CF cells [2, 3].”
Furin seems to be a very important word in COVID.
Fig. 1: SARS-CoV-2 and cystic fibrosis. Fun image!
https://www.nature.com/articles/s41435-020-0103-y/figures/1
“The spike protein on the virion binds to the ACE2 cell membrane protein. Cellular entry is facilitated by the TMPRSS2 and furin enzymes, one or more of which may be altered in CF.”
Keep going –
“Once inside the cell, viral processing, may be influenced either by overactive inflammation and/or CF-affected cellular processes including autophagy, mitophagy, endosomal function and cellular metabolism, which may all be co-opted by COVID-19 for viral replication.
The role of furin in viral pathogenesis has recently been reviewed and the authors state that ‘the pathogenesis of some CoVs has been previously related to the presence of a furin-like cleavage site in the S-protein sequence’ [17]. For example, the insertion of a similar cleavage site in the infectious bronchitis virus (IBV) S-protein results in higher pathogenicity, pronounced neural symptoms and neurotropism in infected chickens.
Thus, it is entirely plausible that furin activity may be a key factor in COVID-19 infections and the testing of furin inhibitors as therapeutic agents will be important in future studies [18]. The SARS-CoV-2 virus is reported to mimic the proteolytic activation of ENaC, an ion channel which is significantly upregulated in CF, where it drives inflammation and is critical to airway surface liquid homeostasis [19].”
Which drives the cytokine storm.
My understanding, SARS-CoV-2 is trying to mimic the epithelial sodium channels (ENaC), but in CF patients, it is deregulated. The way in which the CF cells are designed, hence, the mutation, makes it difficult for the virus to attach and spread as efficiently as to non-CFers.
“As yet there are limited data on the response of CF patients to COVID-19 infection, although preliminary information suggests that the course of the disease may be milder than expected.
Globally, from a population of about 100,000 patients, there have been over a hundred cases of COVID-19 infection in people with CF, with around 90% exhibiting relatively few symptoms and complications [20,21,22,23]. Although numbers and outcome may simply reflect effective shielding, it is highly likely that certain regions, such as New York State and Northern Italy, would have reported significant numbers of excess CF-COVID-19 deaths had patients been highly susceptible.
If further clinical experience indicates that the course of COVID-19 infection in CF patients is milder than anticipated, then it could be proposed that the relative protective effect associated with CF might accrue from CF-affected cellular processes linked to viral processing, including autophagy, mitophagy, degradation of mitochondria) endosomal function (organelles sorting and delivering cell material to the surface) and cellular metabolism, which may all be co-opted by COVID-19 for viral replication [24, 25].
We hypothesize that CFTR modulator therapy might also confer an additional benefit to patients with severe respiratory problems due to COVID-19 infection [2, 26].
Cellular corrector medications such as Orkambi, Kalydeco, Symdeco, or Trikafta.
At first glance, one might think that the CF corrector drugs may overcorrect or regulate at such a high-performing rate that would, in this situation make the CF population more susceptible to COVID.
But, CF cells are biological impaired on multiple levels, two to three, and do not have the perfect or exact receptor for COVID, from what the science says so far.
“For example, CFTR modulator therapy given to people with CF helps to restore cellular function, increases airway hydration, reduces oxidative stress, and down-regulates activation of the NLRP3 inflammasome [2].”
Information for smokers:
“The influence of CFTR in non-CF respiratory disease 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 can be reversible by a CFTR potentiator in vitro [27, 28].
Carriers of the (commonest by far) Phe508del mutation found in over 70% of patients have also been reported as having an increased risk of developing chronic bronchitis and bronchiectasis [29].”
For non-CFers and CFers:
“The role of CFTR in COVID-19 needs further elucidation in patients without CF. In an influenza model, the CFTR corrector, lumacaftor, (one of the cell correctors) was found to reverse in vitro down-regulation of CFTR and ENaC following viral infection and to restore airway surface liquid [30,31,32].
Both CFTR and ENaC have been proposed as theoretical cleavage sites for the coronavirus proteinase 3CLpro enzyme, which controls viral replication [33].
The transmembrane protease serine 2 (TMPRSS2), which can facilitate viral entry into the target host cell, also reduces ENaC activity in airway epithelium [34]. The detailed analysis of clinical outcomes in CF affected people may provide clues as to how these factors interact in the real world of COVID-19 disease.
The clinical importance of characterizing the effects of COVID-19 infection in CF patients, and understanding the possible underlying protective effects, could shed light on novel targets and new approaches to antiviral therapy.”
All the science is working together.
“We suggest that clinical trials of modern CF drugs should be explored in those infected by 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 either receive or do not receive modern CF drug combinations, and we also urge all CF registries to collect such case-control data to inform future studies.”
Article published July 1, 2020
Author – Peckham, D., McDermott, M.F., Savic, S. et al. COVID-19 meets Cystic Fibrosis: for better or worse?. Genes Immun (2020). https://doi.org/10.1038/s41435-020-0103-y
A lot of information.
In essence, we have keywords: receptor, furin enzyme, and cytokine storm, among others. 🙂
Remarkable, the number of thoughts and progress and just expandable meaning that has taken place in such a short time.
We will get there.
Much love and please take care of you and you and you.
Note: I removed the block quotations because the letters are darker and harder to see. I will have to look into later.
Work Cited:
https://www.nature.com/articles/s41435-020-0103-y
https://www.niaid.nih.gov/diseases-conditions/covid-19
COVID-19 Cases in Spain Lower in Cystic Fibrosis vs General Population