Cystic fibrosis (CF) is an autosomal recessive genetic disorder which affects mainly the lungs and/or pancreas.1 Currently, cystic fibrosis is known as the most common lethal inherited disease in the Caucasian population.2 People with CF suffer from progressive respiratory complaints along with recurrent airway infections, but also other organ systems are impaired, which leads to malabsorption and infertility. At the moment, the prognosis for CF-patients is poor, mainly due to damage of the respiratory tract by recurrent infection which induce enormous inflammation. Since airway infections play an important role in CF, it raised the question whether this pathology can be related to the newly discovered airway microbiome. This relationship between CF and the airway microbiome will be discussed in this blog. This post will cover everything you need to know about CF to prepare you for the rest of this blog. If you are already an expert on cystic fibrosis, you can sit back and see if you really know everything by scanning through the text below. Let’s start with an introductory video that shows clearly what the impact is of CF;
Epidemiology
So, as mentioned above, CF is a genetic disorder which is inherited in a
autosomal recessive way. (To refresh your memory about autosomal recessive
inheritance, click here) In Caucasian
people, around 1 in 20 is a carrier, and 1 in 2000-3000 is actually affected,
which is significantly higher than in other ethnic backgrounds, such as Asians
or Afro-Americans.1,3
Clinical picture
In the image below, it is shown how symptoms could be manifested in a
patient with CF.
 |
| Figure 1 Manifestations of Cystic Fibrosis. Reference; Kliegman, Robert; Richard M Kliegman (2006) Nelson essentials of pediatrics, St. Louis, Mo: Elsevier Saunders. |
As you can see, there are many different organs involved in CF, but
mainly, it’s a disease of the lungs, intestines and reproductive system. The
symptoms usually first displayed around 6 to 8 months of age and remain for a
life time.1
Prognosis
There has been an enormous increase in
life-expectancy in CF-patients, which has resulted in the fact that actually
80% of the patients born reach adulthood.1 However Life-expectancy in CF-patients is still poor; currently, it is around 40 years of age.12 The poor prognosis is
mainly due to respiratory failure, which is a result from chronic damage that
is induced by the hyperinflammatory response against infection.1,7,8
Pathophysiology
There are several genetic defects associated with cystic fibrosis; those
mutations are in the gene on the long arm of chromosome 7 which codes for the
Cystic Fibrosis Transmembrane conductance Regulator (CFTR). In total, there are more than
2000 mutations described in CFTR.4
However, only 242 are known to be causing CF.5
Why do these
mutations cause disease?
The common pathway that is affected in CF, is either low expression of
this protein or dysfunction of CFTR,
which is responsible for chloride and bicarbonate transport in different
organs. In the lungs, CFTR is important for secretion of chloride and
bicarbonate, while in the skin, it is important for resorption. For example, in
the lungs, when there is dysfunctionality of CFTR, the chloride can’t be
secreted. Consequently, sodium won’t be excreted because of electric balance
and this will result in less secretion of water due to osmosis. Eventually,
this will result into sticky mucus in the lungs.6
 |
| Figure 2 CFTR function and dysfunction. Author unknown |
There is a certain classification of mutations based on the quantity,
activity and stability of CFTR. For example, class I mutations have no CFTR
protein synthesis at all, while class IV mutations result in an impairment of CFTR
conductance.
 |
| Figure 3 Classes of mutations in CF. Reference: Quintana-Callego E et al. CFTR protein repair therapy in cystic fibrosis. Available from: http://www.archbronconeumol.org/en/cftr-protein-repair-therapy-in/articulo/S1579212914000731/) |
Symptomatic disease can be explained by different mechanisms. First of
all, due to the sticky mucus, the mucociliary capacity of the epithelium is impaired.
Consequently, certain bacteria, like Pseudomonas Aeruginosa, can colonize the
lung more easily.8 Moreover, it has been shown that the innate
immune system is not working well. The innate immune system normally consist of
antimicrobial peptides (AMP’s), complement and myeloid cells that provide a
first line of protection of the lungs against colonization with pathogens.9
In CF-patients, the immune system is altered on different levels; it has
been shown that there is a hyperinflammatory response without sufficient
clearance of the pathogen. This is called the cystic fibrosis hyperinflammatory controversy. Some studies have
shown that the lack of CFTR results in upregulation of NFκβ-mediated
signalling, which is pro-inflammatory and leads to production of IL-8.10
Below, the signalling and function of NFκβ-mediated signalling is depicted
 |
| Figure 4 NFκβ-mediated signalling. Author unknown |
There are various defects described in the innate immune system of
CF-patients, which may explain the defective clearance of pathogens in the
lungs. One possible explanation is the dysfunction of AMP’s. AMPs are peptides
produced by different cell types, such as airway epithelial cells, after a
pathogen is recognized by Toll-like receptors on the surface of these cells.8,9
The functions of AMP’s are described below; they can both activate the innate
immune system by binding TLR’s in their turn and directly kill pathogens by pore-forming.
 |
| Figure 5 Function of epithelial AMP’s. They have a central role in shaping the innate immune response. The resistance mechanisms are ways how the bacteria could actually evade the AMP’s Reference: Duplantier et al. 2013 Frontiers in Immunology 4(143): 1-14. Available from https://www.frontiersin.org/articles/10.3389/fimmu.2013.00143/full#B55 |
In cystic fibrosis, AMP’s are less functional by structural
conformations due to high acidity of the mucus, which leads to defective
clearance of bacteria.6,7 Another reason for defective clearance is
the a decrease in nitric oxide (NO) due to less transcription of the NOS-2
protein, which normally induces NO in response to inflammation. Decreased
NO-levels are unfavourable, because NO usually prevents binding of P. Aeruginosa
to the airway epithelium.11
Additionally, the mucus has a higher concentration of reactive oxygen
species (ROS), that have not only a damaging effect on the airway, but also promotes
inflammation and inhibits CFTR production.12 It actually makes the
problem even bigger. In the Figure 4, it is shown that ROS can be
pro-inflammatory through NFκβ-mediated signalling.
Last of all, neutrophils and macrophages are also dysfunctional. For
example, macrophages are less able to kill phagocytosed pathogens,15,16.
Neutrophils undergo actually normal maturation and production of for example
IL-8, but still seem to be deficient in killing pathogens, resulting in more
dead neutrophils.8 With a lot of debris due to the deade neutrophils, it is
easier for certain bacteria to colonize. For example, P. Aeruginosa is able to
use this debris to make biofilm (read more about biofilm), which is a protection layer in which bacteria
can remain dormant.13 This makes it a lot more difficult to kill these
bacteria. In CF, neutrophils are also producing more “NET’s (Neutrophil
extracellular traps), that are known to be pro-inflammatory and obstructive.14
We can conclude that the innate immune system is altered, which leads to
hyperinflammation in lung tissue causing damage in the proces.17 This leads to
colonization of different pathogens and therefore shapes the microbiome of the
lung. Another blogpost focuses on the lung microbiome in general and in more specifically CF-patients.
Treatment
At last, I would like to touch upon the treatment modalities in CF. At
the moment, there are a few cornerstones in treatment of CF, which are mainly
based on tackling symptoms and prevent complications. Certain aspects of this
treatment will be explained in further blogposts, such as lung transplantation
in end-stage CF and the use of antibiotics in prevention and treatment of the recurrent infections in CF. But there are also other modalities like
improvement of airway clearance and more innovative therapies that are tackling
CFTR such as gene therapy18,19 and biologicals that improve either
the function of CFTR20, or the expression of CFTR.18
Momentarily, new approaches are being researched, which tackle the
hyperinflammatory response that I described above. For example, we can try to
block the the NFκB-signalling, which leads to less production of IL-8 and less
inflammation.8 Another treatment option is increasing the number of
anti-oxidants, which will neutralize the reactive oxygen species, which will
also lead to a decrease in inflammation. Last of all, we can use antagonists
for the CXCR-1 and CXCR-2 receptors, which are receptors important in
perpetuation of the immune response and induction of NETosis, respectively.8
Tackling these features will break the inflammatory circle, resulting in less
airway damage and therefore less possibilities for pathogens to thrive.
Conclusion
In conclusion, cystic fibrosis is a genetic disease with an enormous
burden of disease and consequences for patients. The most important thing to
understand about this post, is the fact that the altered immune response in CF
can lead to colonization of different pathogens, which can cause inflammation
and damage as a consequence. This is an important feature in order to understand why
the airway microbiome is actually different in CF.
For a recap, you can watch the video below
Written by Jens Krol
Last
update (16/10/2017)
References;
References;
1. Sharma GD (Medscape). Cystic Fibrosis. Last update
31/07/2017. Consulted at 14/10/2017. Available from: https://emedicine.medscape.com/article/1001602-ovn
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2. World Health Organization. Genes and human disease.
Last update unknown. Consulted at 14/10/2017. Available from: http://www.who.int/genomics/public/geneticdiseases/en/index2.html#CF
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Crit Care Med. 1996; 154(5): 1229-1256
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fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008; 7: 179–196
5. CFTR Science. CFTR mutations; 242 are known to be
CF-causing. Last update 01/09/2017. Consulted at 14/10/2017. Available from: https://www.cftrscience.com/?q=cftr-mutations
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