scholarly journals One versus Many: Polymicrobial Communities and the Cystic Fibrosis Airway

mBio ◽  
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.

scholarly journals Recapitulation of polymicrobial communities associated with cystic fibrosis airway infections: a perspective

2019 ◽  
Vol 14 (16) ◽  
pp. 1437-1450 ◽  
Author(s):  
Thomas J O'Brien ◽  
Martin Welch
Keyword(s):  
Cystic Fibrosis ◽  
Metabolic Pathways ◽  
Interspecies Interactions ◽  
Microbial Ecosystems ◽  
Cystic Fibrosis Airway ◽  
Airway Infections ◽  
Infection Models ◽  
Mammalian Infection ◽  
Polymicrobial Communities

The airways of persons with cystic fibrosis are prone to infection by a diverse and dynamic polymicrobial consortium. Currently, no models exist that permit recapitulation of this consortium within the laboratory. Such microbial ecosystems likely have a network of interspecies interactions, serving to modulate metabolic pathways and impact upon disease severity. The contribution of less abundant/fastidious microbial species on this cross-talk has often been neglected due to lack of experimental tractability. Here, we critically assess the existing models for studying polymicrobial infections. Particular attention is paid to 3Rs-compliant in vitro and in silico infection models, offering significant advantages over mammalian infection models. We outline why these models will likely become the ‘go to’ approaches when recapitulating polymicrobial cystic fibrosis infection.

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

2017 ◽  
Vol 200 (4) ◽  
Author(s):  
George A. O'Toole
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Chronic Infections ◽  
Cystic Fibrosis Airway ◽  
Airway Infections ◽  
Culture Independent ◽  
Airway Microbiome ◽  
New Strategies ◽  
The Way

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.

scholarly journals Microbiology of Cystic Fibrosis Airway Disease

2019 ◽  
Vol 40 (06) ◽  
pp. 727-736 ◽  
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.

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

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
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.

scholarly journals Genomic Analysis Identifies NovelPseudomonas aeruginosaResistance Genes under Selection during Inhaled Aztreonam TherapyIn Vivo

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Kathryn McLean ◽  
Duankun Lee ◽  
Elizabeth A. Holmes ◽  
Kelsi Penewit ◽  
Adam Waalkes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Positive Selection ◽  
Single Gene ◽  
Genomic Analysis ◽  
Maximal Activity ◽  
Content Type ◽  
Cystic Fibrosis Airway ◽  
Bacterial Fitness

ABSTRACTInhaled aztreonam is increasingly used for chronicPseudomonas aeruginosasuppression in patients with cystic fibrosis (CF), but the potential for that organism to evolve aztreonam resistance remains incompletely explored. Here, we performed genomic analysis of clonally related pre- and posttreatment CF clinical isolate pairs to identify genes that are under positive selection during aztreonam therapyin vivo. We identified 16 frequently mutated genes associated with aztreonam resistance, the most prevalent beingftsIandampC, and 13 of which increased aztreonam resistance when introduced as single gene transposon mutants. Several previously implicated aztreonam resistance genes were found to be under positive selection in clinical isolates even in the absence of inhaled aztreonam exposure, indicating that other selective pressures in the cystic fibrosis airway can promote aztreonam resistance. Given its potential to confer plasmid-mediated resistance, we further characterized mutantampCalleles and performed artificial evolution ofampCfor maximal activity against aztreonam. We found that naturally occurringampCmutants conferred variably increased resistance to aztreonam (2- to 64-fold) and other β-lactam agents but that its maximal evolutionary capacity for hydrolyzing aztreonam was considerably higher (512- to 1,024-fold increases) and was achieved while maintaining or increasing resistance to other drugs. These studies implicate novel chromosomal aztreonam resistance determinants while highlighting that different mutations are favored during selectionin vivoandin vitro, show thatampChas a high maximal potential to hydrolyze aztreonam, and provide an approach to disambiguate mutations promoting specific resistance phenotypes from those more generally increasing bacterial fitnessin vivo.

scholarly journals 16S rRNA gene sequencing reveals site-specific signatures of the upper and lower airways of cystic fibrosis patients

2017 ◽  
Author(s):  
Sarah K. Lucas ◽  
Robert Yang ◽  
Jordan M. Dunitz ◽  
Holly C. Boyer ◽  
Ryan C. Hunter
Keyword(s):  
Cystic Fibrosis ◽  
Bacterial Communities ◽  
Gene Sequencing ◽  
Microbial Colonization ◽  
Sinus Surgery ◽  
Lower Airway ◽  
Rrna Gene ◽  
Inflammatory Disorder ◽  
Airway Infections ◽  
Lower Airways

ABSTRACTRationaleChronic rhinosinusitis (CRS) is an inflammatory disorder of the sinonasal mucosa associated with microbial colonization. Metastasis of sinus microbiota into the lower airways is thought have significant implications in the development of chronic respiratory disease. However, this dynamic has not been thoroughly investigated in cystic fibrosis (CF) patients, where lower airway infections are the primary driver of patient mortality. Given the high prevalence of CRS in CF patients and the proposed infection dynamic between the upper and lower airways, a better understanding of sinus-lung continuum is warranted.ObjectiveTo compare the microbiome of matched sinus mucus and lung sputum samples from CF subjects undergoing functional endoscopic sinus surgery (FESS) for treatment of CRS.MethodsMucus was isolated from the sinuses and lungs of twelve CF patients undergoing FESS. 16S ribosomal RNA gene sequencing was then performed to compare bacterial communities of the CF lung and sinus niches. Finally, functional profiling was performed to predict bacterial metagenomes from the 16S dataset, and was used to compare pathogenic bacterial phenotypes between the upper and lower airways.Measurements and Main ResultsBacterial richness was comparable between airway sites, though sinus and lung environments differed in community evenness, with the sinuses harboring a higher prevalence of dominant microorganisms. Beta diversity metrics also revealed that samples clustered more consistently by airway niche rather than by individual. Finally, predicted metagenomes showed that anaerobic metabolism was enriched in the lung environment, while genes associated with both biofilm formation and Gram identity were not variable between sites.ConclusionsSinus and lung microbiomes are distinct with respect to richness and evenness, while sinus communities have a higher incidence of a dominant taxon. Additionally, ordination analyses point to sinus and lung environments as being stronger determinants of microbial community structure than the individual patient. Finally, BugBase-predicted metagenomes revealed anaerobic phenotypes to be in higher abundance in the lung relative to the sinuses. Our findings indicate that while the paranasal sinuses and lungs may still comprise a unified airway in which lower airways are seeded by sinus microbiota, these discrete airway microenvironments harbor distinct bacterial communities.

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