Case Studies of the Spatial Heterogeneity of DNA Viruses in the Cystic Fibrosis Lung

Willner, Dana; Haynes, Matthew; Furlan, Mike; Hanson, Nicole; Kirby, Breeann; Lim, Yan Wei; Rainey, Paul B.; Schmieder, Robert; Youle, Merry; Conrad, Dan; Rohwer, Forest

doi:10.1165/rcmb.2011-0253oc

Cited by 95 publications

(80 citation statements)

References 34 publications

(33 reference statements)

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“…Interestingly, nonhomogeneity of inflammation has long been observed in the setting of CF, as assessed both by radiologic imaging and by regional BAL of chronically infected patients (32,33). Recent studies examining explanted lungs of CF patients undergoing lung transplantation have shown that bacterial distribution within the lungs also is spatially heterogeneous (34), a pattern likewise seen for viral DNA (35). Such studies provide the opportunity to test whether spatially distinct populations of a specific CF pathogen, such as P. aeruginosa, show genetic and phenotypic heterogeneity in features such as T3SS expression (36), a possibility suggested by the coisolation of T3SS-positive and -negative P. aeruginosa from the sputum of CF patients (16).…”

Section: Discussionmentioning

confidence: 99%

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Czechowska¹,

McKeithen-Mead

Moussawi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Bacterial pathogens frequently use type 3 secretion systems (T3SS) to counteract host immune responses to infection. T3SS expression is associated with increased virulence of Pseudomonas aeruginosa in humans and in animal models, but T3SS-negative bacteria often are isolated from acutely and chronically infected patients. We tested whether T3SS-negative bacteria could “cheat” during mixed infections with T3SS-positive bacteria in a murine model of acute pneumonia. Bacterial cheating occurred in the inflamed lung but only when T3SS-positive bacteria secreted the phospholipase A 2 effector, Exotoxin U. Phenotypically T3SS-expressing and –non-expressing bacteria co-exist within P. aeruginosa populations, suggesting that bacterial cheating might allow T3SS-negative organisms to establish themselves within a host.

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Section: Discussionmentioning

confidence: 99%

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Czechowska¹,

McKeithen-Mead

Moussawi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Viruses play a major role in chronic inflammatory diseases of the lung such as asthma, COPD, and CF, although few studies have been performed to evaluate the airway virome (95,96). Improved understanding of the nonbacterial composition of the microbiome will be essential for completing our understanding the interactions of the microbial community in its entirety in the settings of health and disease.…”

Section: Lessons Learned From the Study Of Airway Microbiota In Lung mentioning

confidence: 99%

“…To this end, whole-genome sequencing (shotgun metagenomics) is a more promising approach. Using metagenomics to evaluate regional differences in the virome in the lung of advanced CF, it has been suggested that the apical lobes of patients with stable CF may house a unique virome characterized by extremely low richness and the predominance of eukaryotic viruses, such as herpesvirus, anellovirus, and papillomavirus (95). Interestingly, on the basis of these data, the most affected areas do not seem to have bacteriophages.…”

Section: Lessons Learned From the Study Of Airway Microbiota In Lung mentioning

confidence: 99%

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

2014

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Microbes are readily cultured from epithelial surfaces of the skin, mouth, and colon. In the last 10 years, culture-independent DNAbased techniques demonstrated that much more complex microbial communities reside on most epithelial surfaces; this includes the lower airways, where bacterial culture had failed to reliably demonstrate resident bacteria. Exposure to a diverse bacterial environment is important for adequate immunological development. The most common microbes found in the lower airways are also found in the upper airways. Increasing abundance of oral characteristic taxa is associated with increased inflammatory cells and exhaled nitric oxide, suggesting that the airway microbiome induces an immunological response in the lung. Furthermore, rhinovirus infection leads to outgrowth of Haemophilus in patients with chronic obstructive pulmonary disease, and human immunodeficiency virus-infected subjects have more Tropheryma whipplei in the lower airway, suggesting a bidirectional interaction in which the host immune defenses also influence the microbial niche. Quantitative and/or qualitative changes in the lung microbiome may be relevant for disease progression and exacerbations in a number of pulmonary diseases. Future investigations with longitudinal follow-up to understand the dynamics of the lung microbiome may lead to the development of new therapeutic targets.

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“…are most frequently observed, but more drug-resistant species, such as Scedosporium azoospermia, are becoming common (14). The viruses include both those that potentially infect humans as well as bacteriophages (phages) that prey upon the bacterial community (15).…”

Section: The Microbiota Of the Cf Lung Ecosystemmentioning

confidence: 99%

“…Based on the 16S ribosomal RA (rRNA) sequences present, this approach has shown not only that the microbial communities are more diverse than previously appreciated, but that this diversity may peak during adolescence, before significant structural remodeling of the lung (16,17). Recent metagenomic studies characterizing the microbial and viral communities within lung tissue dissected from distinct lung regions have added the spatial dimension, reporting that different lobes housed distinctly different communities, thus further complicating clinical treatment (15,18).…”

Section: The Microbiota Of the Cf Lung Ecosystemmentioning

confidence: 99%

Cystic Fibrosis Therapy: A Community Ecology Perspective

Conrad

Haynes

Salamon³

et al. 2013

Am J Respir Cell Mol Biol

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121

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and 7 Rainbow Rock, Ocean View, Hawaii Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host's immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical and biological. Recent cultureindependent assessments of the airway microbial and viral communities demonstrated that the CF airway infection is considerably more complex and dynamic than previously appreciated. Understanding the ecological and evolutionary pressures that shape these communities is critically important for the optimal use of current therapies (in both the choice of therapy and timing of administration) and the development of newer strategies. The climax-attack model (CAM) presented here, grounded in basic ecological principles, postulates the existence of two major functional communities. The attack community consists of transient viral and microbial populations that induce strong innate immune responses. The resultant intense immune response creates microenvironments that facilitate the establishment of a climax community that is slower-growing and inherently resistant to antibiotic therapy. Newer methodologies, including sequence-based metagenomic analysis, can track not only the taxonomic composition but also the metabolic capabilities of these changing viral and microbial communities over time. Collecting this information for CF airways will enable the mathematical modeling of microbial community dynamics during disease progression. The resultant understanding of airway communities and their effects on lung physiology will facilitate the optimization of CF therapies.

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Case Studies of the Spatial Heterogeneity of DNA Viruses in the Cystic Fibrosis Lung

Cited by 95 publications

References 34 publications

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Cheating by type 3 secretion system-negative Pseudomonas aeruginosa during pulmonary infection

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

Cystic Fibrosis Therapy: A Community Ecology Perspective

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