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Review
. 2016 Dec 5;16(1):174.
doi: 10.1186/s12890-016-0339-5.

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Anjali Y Bhagirath  1   2 , Yanqi Li  1   2 , Deepti Somayajula  1   2 , Maryam Dadashi  1   2 , Sara Badr  3   2 , Kangmin Duan  4   5   6
Affiliations
Review

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

Anjali Y Bhagirath et al. BMC Pulm Med. .

Abstract

Background: The airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well as a distinct microbiota. Pseudomonas aeruginosa is recognized as one of the most important pulmonary pathogens and the predominant cause of morbidity and mortality in CF. A multifarious interplay between the host, pathogens, microbiota, and the environment shapes the course of the disease. There have been several excellent reviews detailing CF pathology, Pseudomonas and the role of environment in CF but only a few reviews connect these entities with regards to influence on the overall course of the disease. A holistic understanding of contributing factors is pertinent to inform new research and therapeutics.

Discussion: In this article, we discuss the deterministic alterations in lung physiology as a result of CF. We also revisit the impact of those changes on the microbiota, with special emphasis on P. aeruginosa and the influence of other non-genetic factors on CF. Substantial past and current research on various genetic and non-genetic aspects of cystic fibrosis has been reviewed to assess the effect of different factors on CF pulmonary infection. A thorough review of contributing factors in CF and the alterations in lung physiology indicate that CF lung infection is multi-factorial with no isolated cause that should be solely targeted to control disease progression. A combinatorial approach may be required to ensure better disease outcomes.

Conclusion: CF lung infection is a complex disease and requires a broad multidisciplinary approach to improve CF disease outcomes. A holistic understanding of the underlying mechanisms and non-genetic contributing factors in CF is central to development of new and targeted therapeutic strategies.

Keywords: CFTR; Cystic fibrosis; Host-pathogen interaction; Microbiome; Non-genetic influences.

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Figures

Fig. 1
Fig. 1
Two-dimensional representation of CFTR channel and homology models. a A cartoon representation of CFTR. CFTR is composed of two membrane spanning domains (MSDs), each linked through intracellular loops (ICLs) and extracellular loops (ECLs) (not shown here) to nucleotide binding domains (NBD1 and 2) (red). Unique to CFTR, NBD1 is connected to the MSD2 by a regulatory domain (R). b The three-dimensional homology model for CFTR based on Sav1866 structure (2HYD) [–28]. MSD1 contains transmembrane helices (TM) 1–6 and MSD2 contains TMs 7–12. The amino N terminus and carboxyl-terminus are labelled respectively as N and C in yellow and shown circles. Insert shows F508A mutation in NBD1 crystal structure (1XMI) seen in gray [28]. c CFTR is shown in its outward facing (extracellular) conformation
Fig. 2
Fig. 2
The different anatomical divisions of human respiratory system relevant to CF lung disease. Environmental factors such as oxygen and nutrient availability vary significantly in different regions of the human respiratory system and influence disease outcomes. a The airway can be divided primarily into the upper and lower respiratory tract. b Lower respiratory tract is further divided into conductive zone and the respiratory zone. The conducting zones consist of trachea, primary and terminal bronchioles. The conducting zones are secretory in function. The respiratory zones perform the function of air exchange and consist of respiratory bronchioles and alveolar sacs
Fig. 3
Fig. 3
Anatomical distribution of mucus secreting cells in normal airways and pathological alterations in CF. a Mucus is secreted by submucosal glands in the conductive zone and paranasal sinuses. The submucosal glands go on decreasing towards the lowest components of the respiratory zone. In healthy individuals, the cilia of the epithelial cells clear irritants and microorganisms, trapping them in the thin fluidic mucus and clearing by rhythmic ciliary beating upwards known as mucous escalator. In CF, the airway surface liquid layer thins and the mucus comes in contact with cilia resulting in ciliary dyskinesis, causing poor clearance of bacteria which exacerbates inflammation. b Schematic drawing of a single submucosal gland shows serous acini, mucus tubules, and collecting duct. Secretion of water across the epithelium of airway glands is driven predominantly by active secretion of chloride and bicarbonate. The CFTR-dependent water-secreting pathway is defective in CF. Figure adapted from previous publications [54, 55, 57, 59]
Fig. 4
Fig. 4
P. aeruginosa features relevant to pathogenicity and adaptation. P. aeruginosa produces an impressive array of virulence factors to counteract host defenses and facilitate inter-bacterial competition. The expression of virulence genes in P. aeruginosa is controlled by extremely complex regulatory circuits and signaling systems. The diagram outlines key features relevant to its pathogenicity and survival in vivo
Fig. 5
Fig. 5
Prevalence of respiratory pathogens and antimicrobial resistant strains in patients with CF. As of 2003, P. aeruginosa is no longer the most common pathogen cultured in individuals with CF in USA. There has been an observable increase in the prevalence of S. aureus and Strenotrophomonas maltophilia. Figure reproduced with permision from Cystic Fibrosis Foundation Patient Registry, Cystic Fibrosis Foundation. Annual Data Report 2014. Bethesda, MD, USA [143]
Fig. 6
Fig. 6
Prevalence of antimicrobial resistant strains in CF patients. An increase in the rates of multidrug-resistant P. aeruginosa infection has been observed in older CF patients in USA. Figure reproduced with permissions from the Cystic Fibrosis Foundation Patient Registry, Cystic Fibrosis Foundation. Annual Data Report 2014. Bethesda, MD, USA [143]
Fig. 7
Fig. 7
A potential mechanism of the transition from stable state to pulmonary exacerbation. Without much of a change in bacterial loads, the changes of the pathogenicity triggered by the host environment and/or host-microbiota interaction could lead to a transition from stable state to pulmonary exacerbation
Fig. 8
Fig. 8
CF airway epithelium and pathogen adaptation. Defective CFTR leads to decreased airway surface liquid (ASL) layer. This facilitates microbial colonization and airway inflammation. Pathogen-associated molecular patterns (PAMPs) activate Toll-like receptor (TLR) signaling to activate Interleukin-8 (IL-8) and therefore to recruit polymorphonuclear neutrophils (PMNs). The increasing PMNs result in oxidative stress within the airways by forming reactive oxygen species (ROS). The increased oxidative stress further activates the mitogen activated protein kinase pathway, activating IL-8 and thus recruiting more PMNs. Mutated CFTR in the epithelial cells is unable to channel the antioxidants Glutathione (GSH) and thiocyanate (SCN−) into the airway, limiting their ability to counteract the oxidative stress. TLR expression and signaling is also altered in CF epithelium. Expression of TLR2 and TLR5 at the apical surface is increased, whereas TLR4 expression is limited to endosome (not shown here). NF-κB in CF airway epithelial cells is constitutively activated, resulting in the production of inflammatory cytokines including IL-8 and granulocyte macrophage colony stimulating factor (GM-CSF). This also leads to recruitment of PMNs independent of TLR’s interaction with the adaptor protein MyD88. Bacterial PAMPs further increase NF-κB signaling through activation of TLR-MyD88 signaling. The inhaled bacteria start interacting and aggregating to form biofilms. P. aeruginosa also releases outer membrane vesicles containing CF inhibitory factor (Cif), a protein that further inhibits the recycling of CFTR in the host further contributing to the cycle of hyper-inflammation and bacterial colonization
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