Cystic Fibrosis Airway Microbiome: Overturning the Old, Opening the Way for the New

ABSTRACTThe genetic disease cystic fibrosis (CF) is associated with chronic airway infections that are a proximal cause of death in many patients with this affliction. Classic microbiology studies focusing on canonical pathogens resulted in the development of a common set of views regarding the nature of the airway infections associated with this disease, and these ideas have influenced everything from the way infections are treated to how clinical trials for new CF-targeted antibiotics are designed and the focus of CF-related research topics. Recent culture-independent studies have prompted us to rethink, and in some cases discard, some of these long-held views. In this piece, I argue that an updated view of the complicated chronic infections associated with CF, thanks in large part to culture-independent studies of sputum and bronchoalveolar lavage fluid samples, should be leveraged to develop new strategies to treat these recalcitrant infections.

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One versus Many: Polymicrobial Communities and the Cystic Fibrosis Airway

mBio ◽

10.1128/mbio.00006-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Fabrice Jean-Pierre ◽

Arsh Vyas ◽

Thomas H. Hampton ◽

Michael A. Henson ◽

George A. O’Toole

Keyword(s):

Cystic Fibrosis ◽

Species Interactions ◽

Rrna Gene ◽

Microbial Composition ◽

Community Function ◽

Cystic Fibrosis Airway ◽

Airway Infections ◽

Culture Independent ◽

Polymicrobial Communities

ABSTRACT Culture-independent studies have revealed that chronic lung infections in persons with cystic fibrosis (pwCF) are rarely limited to one microbial species. Interactions among bacterial members of these polymicrobial communities in the airways of pwCF have been reported to modulate clinically relevant phenotypes. Furthermore, it is clear that a single polymicrobial community in the context of CF airway infections cannot explain the diversity of clinical outcomes. While large 16S rRNA gene-based studies have allowed us to gain insight into the microbial composition and predicted functional capacities of communities found in the CF lung, here we argue that in silico approaches can help build clinically relevant in vitro models of polymicrobial communities that can in turn be used to experimentally test and validate computationally generated hypotheses. Furthermore, we posit that combining computational and experimental approaches will enhance our understanding of mechanisms that drive microbial community function and identify new therapeutics to target polymicrobial infections.

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Polymicrobial Interactions in the Cystic Fibrosis Airway Microbiome Impact the Antimicrobial Susceptibility of Pseudomonas aeruginosa

Antibiotics ◽

10.3390/antibiotics10070827 ◽

2021 ◽

Vol 10 (7) ◽

pp. 827

Author(s):

Emma Reece ◽

Pedro H. de Almeida Bettio ◽

Julie Renwick

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Airway Disease ◽

Chronic Infections ◽

Sensitivity Testing ◽

Antimicrobial Sensitivity ◽

Cystic Fibrosis Airway ◽

Airway Microbiome ◽

Diverse Community

Pseudomonas aeruginosa is one of the most dominant pathogens in cystic fibrosis (CF) airway disease and contributes to significant inflammation, airway damage, and poorer disease outcomes. The CF airway is now known to be host to a complex community of microorganisms, and polymicrobial interactions have been shown to play an important role in shaping P. aeruginosa pathogenicity and resistance. P. aeruginosa can cause chronic infections that once established are almost impossible to eradicate with antibiotics. CF patients that develop chronic P. aeruginosa infection have poorer lung function, higher morbidity, and a reduced life expectancy. P. aeruginosa adapts to the CF airway and quickly develops resistance to several antibiotics. A perplexing phenomenon is the disparity between in vitro antimicrobial sensitivity testing and clinical response. Considering the CF airway is host to a diverse community of microorganisms or ‘microbiome’ and that these microorganisms are known to interact, the antimicrobial resistance and progression of P. aeruginosa infection is likely influenced by these microbial relationships. This review combines the literature to date on interactions between P. aeruginosa and other airway microorganisms and the influence of these interactions on P. aeruginosa tolerance to antimicrobials.

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Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.548613 ◽

2021 ◽

Vol 11 ◽

Author(s):

Buqing Yi ◽

Alexander H. Dalpke ◽

Sébastien Boutin

Keyword(s):

Cystic Fibrosis ◽

Essential Role ◽

Genetic Defect ◽

Limiting Factors ◽

Major Life ◽

Treatment Scheme ◽

Cystic Fibrosis Airway ◽

Airway Infections ◽

Airway Microbiome ◽

Airway Physiology

The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.

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The polymicrobial nature of airway infections in cystic fibrosis: Cangene Gold Medal LectureThis article is based on a presentation by Dr. Christopher Sibley at the 60th Annual Meeting of the Canadian Society of Microbiologists in Hamilton, Ontario, on 15 June 2010. Dr. Sibley was the recipient of the 2010 Cangene Gold Medal as the Canadian Graduate Student Microbiologist of the Year, an annual award sponsored by Cangene Corporation intended to recognize excellence in graduate research.

Canadian Journal of Microbiology ◽

10.1139/w10-105 ◽

2011 ◽

Vol 57 (2) ◽

pp. 69-77 ◽

Cited By ~ 37

Author(s):

Christopher D. Sibley ◽

Michael G. Surette

Keyword(s):

Cystic Fibrosis ◽

Microbial Communities ◽

Gold Medal ◽

Emergent Properties ◽

Host Interactions ◽

Airway Infections ◽

Future Challenges ◽

Culture Independent ◽

Airway Microbiome ◽

Dynamic Communities

Microbial communities characterize the airways of cystic fibrosis (CF) patients. Members of these diverse and dynamic communities can be thought of as pathogens, benign commensals, or synergens — organisms not considered pathogens in the traditional sense but with the capacity to alter the pathogenesis of the community through microbe–microbe or polymicrobe–host interactions. Very few bacterial pathogens have been implicated as clinically relevant in CF; however, the CF airway microbiome can be a reservoir of previously unrecognized but clinically relevant organisms. A combination of culture-dependent and culture-independent approaches provides a more comprehensive perspective of CF microbiology than either approach alone. Here we review these concepts, highlight the future challenges for CF microbiology, and discuss the implications for the management of CF airway infections. We suggest that the success of treatment interventions for chronic CF lung disease will rely on the context of the microbes within microbial communities. The microbiology of CF airways may serve as a model to investigate the emergent properties of other clinically relevant microbial communities in the human body.

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Microbiology of Cystic Fibrosis Airway Disease

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-1698464 ◽

2019 ◽

Vol 40 (06) ◽

pp. 727-736 ◽

Cited By ~ 5

Author(s):

Ana C. Blanchard ◽

Valerie J. Waters

Keyword(s):

Cystic Fibrosis ◽

Burkholderia Cepacia ◽

Treatment Options ◽

Airway Disease ◽

Burkholderia Cepacia Complex ◽

Pulmonary Infections ◽

Lung Function Decline ◽

Cystic Fibrosis Airway ◽

Airway Infections ◽

Culture Independent

AbstractAlthough survival of individuals with cystic fibrosis (CF) has been continuously improving for the past 40 years, respiratory failure secondary to recurrent pulmonary infections remains the leading cause of mortality in this patient population. Certain pathogens such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and species of the Burkholderia cepacia complex continue to be associated with poorer clinical outcomes including accelerated lung function decline and increased mortality. In addition, other organisms such as anaerobes, viruses, and fungi are increasingly recognized as potential contributors to disease progression. Culture-independent molecular methods are also being used for diagnostic purposes and to examine the interaction of microorganisms in the CF airway. Given the importance of CF airway infections, ongoing initiatives to promote understanding of the epidemiology, clinical course, and treatment options for these infections are needed.

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miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production

European Respiratory Journal ◽

10.1183/09031936.00163414 ◽

2015 ◽

Vol 46 (5) ◽

pp. 1350-1360 ◽

Cited By ~ 36

Author(s):

Irene K. Oglesby ◽

Sebastian F. Vencken ◽

Raman Agrawal ◽

Kevin Gaughan ◽

Kevin Molloy ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Protein Production ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Airway Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Airway Epithelial ◽

Bronchial Epithelial ◽

Cystic Fibrosis Airway

Interleukin (IL)-8 levels are higher than normal in cystic fibrosis (CF) airways, causing neutrophil infiltration and non-resolving inflammation. Overexpression of microRNAs that target IL-8 expression in airway epithelial cells may represent a therapeutic strategy for cystic fibrosis.IL-8 protein and mRNA were measured in cystic fibrosis and non-cystic fibrosis bronchoalveolar lavage fluid and bronchial brushings (n=20 per group). miRNAs decreased in the cystic fibrosis lung and predicted to target IL-8 mRNA were quantified in βENaC-transgenic, cystic fibrosis transmembrane conductance regulator (Cftr)-/- and wild-type mice, primary cystic fibrosis and non-cystic fibrosis bronchial epithelial cells and a range of cystic fibrosis versus non-cystic fibrosis airway epithelial cell lines or cells stimulated with lipopolysaccharide, Pseudomonas-conditioned medium or cystic fibrosis bronchoalveolar lavage fluid. The effect of miRNA overexpression on IL-8 protein production was measured.miR-17 regulates IL-8 and its expression was decreased in adult cystic fibrosis bronchial brushings, βENaC-transgenic mice and bronchial epithelial cells chronically stimulated with Pseudomonas-conditioned medium. Overexpression of miR-17 inhibited basal and agonist-induced IL-8 protein production in F508del-CFTR homozygous CFTE29o− tracheal, CFBE41o− and/or IB3 bronchial epithelial cells.These results implicate defective CFTR, inflammation, neutrophilia and mucus overproduction in regulation of miR-17. Modulating miR-17 expression in cystic fibrosis bronchial epithelial cells may be a novel anti-inflammatory strategy for cystic fibrosis and other chronic inflammatory airway diseases.

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Within-Host Evolution of Pseudomonas aeruginosa Reveals Adaptation toward Iron Acquisition from Hemoglobin

mBio ◽

10.1128/mbio.00966-14 ◽

2014 ◽

Vol 5 (3) ◽

Cited By ~ 88

Author(s):

Rasmus Lykke Marvig ◽

Søren Damkiær ◽

S. M. Hossein Khademi ◽

Trine M. Markussen ◽

Søren Molin ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Iron Acquisition ◽

Chronic Infections ◽

Content Type ◽

Mortality And Morbidity ◽

Airway Infections ◽

Host Evolution ◽

Promoter Mutations

ABSTRACTPseudomonas aeruginosaairway infections are a major cause of mortality and morbidity of cystic fibrosis (CF) patients. In order to persist,P. aeruginosadepends on acquiring iron from its host, and multiple different iron acquisition systems may be active during infection. This includes the pyoverdine siderophore and thePseudomonasheme utilization (phu) system. While the regulation and mechanisms of several iron-scavenging systems are well described, it is not clear whether such systems are targets for selection during adaptation ofP. aeruginosato the host environment. Here we investigated the within-host evolution of the transmissibleP. aeruginosaDK2 lineage. We found positive selection for promoter mutations leading to increased expression of thephusystem. By mimicking conditions of the CF airwaysin vitro, we experimentally demonstrate that increased expression ofphuRconfers a growth advantage in the presence of hemoglobin, thus suggesting thatP. aeruginosaevolves toward iron acquisition from hemoglobin. To rule out that this adaptive trait is specific to the DK2 lineage, we inspected the genomes of additionalP. aeruginosalineages isolated from CF airways and found similar adaptive evolution in two distinct lineages (DK1 and PA clone C). Furthermore, in all three lineages,phuRpromoter mutations coincided with the loss of pyoverdine production, suggesting that within-host adaptation toward heme utilization is triggered by the loss of pyoverdine production. Targeting heme utilization might therefore be a promising strategy for the treatment ofP. aeruginosainfections in CF patients.IMPORTANCEMost bacterial pathogens depend on scavenging iron within their hosts, which makes the battle for iron between pathogens and hosts a hallmark of infection. Accordingly, the ability of the opportunistic pathogenPseudomonas aeruginosato cause chronic infections in cystic fibrosis (CF) patients also depends on iron-scavenging systems. While the regulation and mechanisms of several such iron-scavenging systems have been well described, not much is known about how the within-host selection pressures act on the pathogens’ ability to acquire iron. Here, we investigated the within-host evolution ofP. aeruginosa, and we found evidence thatP. aeruginosaduring long-term infections evolves toward iron acquisition from hemoglobin. This adaptive strategy might be due to a selective loss of other iron-scavenging mechanisms and/or an increase in the availability of hemoglobin at the site of infection. This information is relevant to the design of novel CF therapeutics and the development of models of chronic CF infections.

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