Cystic Fibrosis Therapy: A Community Ecology Perspective

Conrad, Dan; Haynes, Matthew; Salamon, Peter; Rainey, Paul B.; Youle, Merry; Rohwer, Forest

doi:10.1165/rcmb.2012-0059ps

Cited by 96 publications

(132 citation statements)

References 59 publications

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“…WinCF and the climax and attack model (CAM) The CAM proposed that there are two functionally different microbial communities in the CF lungs (Conrad et al, 2012). Growth of the Attack Community, consisting of transient viral and microbial populations, is predicted to induce strong immune responses, which create microenvironments that facilitate establishment of a Climax community that is slower growing and inherently resistant to antibiotic therapy (Conrad et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Growth of the Attack Community, consisting of transient viral and microbial populations, is predicted to induce strong immune responses, which create microenvironments that facilitate establishment of a Climax community that is slower growing and inherently resistant to antibiotic therapy (Conrad et al, 2012). Metagenomics studies have shown that the core physiology of the CF microbial community contains both respiratory and fermentative pathways for energy generation .…”

Section: Discussionmentioning

confidence: 99%

“…These communities shape microenvironments within the lung with their own biological, chemical and physical characteristics. These microenvironments allow for the application of fundamental principles of microbial ecology (Yang et al, 2011;Conrad et al, 2012). For example, synergistic and antagonistic behavior between different CF pathogens has been described (Duan et al, 2003;Harrison, 2007;Sibley et al, 2008;Mitchell et al, 2010;Yang et al, 2011;Venkataraman et al, 2014), and the microbial community has been proposed to contain stable and disturbed states, much like those in classical ecology (Conrad et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…These microenvironments allow for the application of fundamental principles of microbial ecology (Yang et al, 2011;Conrad et al, 2012). For example, synergistic and antagonistic behavior between different CF pathogens has been described (Duan et al, 2003;Harrison, 2007;Sibley et al, 2008;Mitchell et al, 2010;Yang et al, 2011;Venkataraman et al, 2014), and the microbial community has been proposed to contain stable and disturbed states, much like those in classical ecology (Conrad et al, 2012). Known chemical characteristics of the CF lung include lowered pH (Tate et al, 2002;Pezzulo et al, 2012), low oxygen tensions (Worlitzsch et al, 2002) and high levels of amino acids, nitrate, iron and phenazines (Grasemann et al, 1998;Jones et al, 2000;Palmer et al, 2007;Ghio et al, 2012;Hunter et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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There is a poor understanding of how the physiology of polymicrobial communities in cystic fibrosis (CF) lungs contributes to pulmonary exacerbations and lung function decline. In this study, a microbial culture system based on the principles of the Winogradsky column (WinCF system) was developed to study the physiology of CF microbes. The system used glass capillary tubes filled with artificial sputum medium to mimic a clogged airway bronchiole. Chemical indicators were added to observe microbial physiology within the tubes. Characterization of sputum samples from seven patients showed variation in pH, respiration, biofilm formation and gas production, indicating that the physiology of CF microbial communities varied among patients. Incubation of homogenized tissues from an explant CF lung mirrored responses of a Pseudomonas aeruginosa pure culture, supporting evidence that end-stage lungs are dominated by this pathogen. Longitudinal sputum samples taken through two exacerbation events in a single patient showed that a two-unit drop in pH and a 30% increase in gas production occurred in the tubes prior to exacerbation, which was reversed with antibiotic treatment. Microbial community profiles obtained through amplification and sequencing of the 16S rRNA gene showed that fermentative anaerobes became more abundant during exacerbation and were then reduced during treatment where P. aeruginosa became the dominant bacterium. Results from the WinCF experiments support the model where two functionally different CF microbial communities exist, the persistent Climax Community and the acute Attack Community. Fermentative anaerobes are hypothesized to be the core members of the Attack Community and production of acidic and gaseous products from fermentation may drive developing exacerbations. Treatment targeting the Attack Community may better resolve exacerbations and resulting lung damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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“…The latter is tempered by the idiosyncratic nature of information gathering and translation into a rational treatment. Related perspectives have recently been discussed for parasites [6], pathogenic bacteria (e.g., [7]), and cancer [8,9]. Figure 1 shows an oversimplified depiction of one type of disease ecosystem: the cancer microenvironment.…”

Section: The Disease Ecosystemmentioning

confidence: 99%

Six wedges to curing disease

Hochberg

2017

Preprint

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Abstract.One of the great challenges in ecology and evolutionary biology is to explain disease, whether caused by infectious agents such as parasites and pathogens, or by the deterioration or transformation of cellular behavior and function, a prime example of the latter being cancer. Decades of observation and research suggest that successfully treating disease requires insights into how the environment mediates the interactions between disease causing agents (DCAs) and diseased individuals. A major finding is that single factor, targeted therapies are not only likely to fail in controlling or eradicating many DCAs, but are also likely to select for resistance, reducing options for subsequent treatment attempts, and in cases of infectious DCAs, rendering therapeutic agents (e.g., antibiotics) obsolete.I argue that meeting the growing challenge of treating disease in agriculture and animal husbandry, in protected and domesticated species, wildlife, and in the human population will require a fundamental understanding of ecological interactions at sites of infection or disease. I discuss different ways in which components of such disease ecosystems mediate DCA and therapeutic dynamics and resistance evolution, and derive a very simple mathematical criterion for therapeutic success. I then touch on how fundamental insights as revealed by the processes of evolutionary rescue and competitive release can help understand why therapies succeed or fail. Finally, I present six "wedges" that can each contribute alone, or as part of multi-pronged approaches to successfully treating disease. The Magic BulletDespite remarkable progress in prevention and treatment, the impacts of diseases in agriculture and animal husbandry, and on protected and domesticated species, wildlife, and human health are likely to intensify into the 21 st century. Humans in particular are increasingly in contact with each other and with wildlife, treated with drug regimens that select for resistance, and adopt life-styles or are exposed to environments that render them more susceptible to infectious diseases and more likely to get cellular diseases such as cancers.For many clinicians the Holy Grail is to discover the Ehrlichian "Magic Bullet"-a drug that will target the disease-causing agents (DCAs) and cure disease. Intuitively, the most effective way to reduce DCAs is to "hit hard and fast". That is, more drug means more kill within the tolerance limits of the patient. Rapid administration of the drug means forestalling further DCA growth and associated symptoms, but also reducing the probability of the appearance of resistant mutant strains. Despite decades of research on pest and disease control (much of it with an ecological basis) this approach and the many alternatives described below remain highly controversial (e.g., [1]).The Magic Bullet may be shortsighted for another reason. What will cure most patients may not be optimal for the general population in which resistant variants may emerge and spread 1 . This problem is in many ways similar...

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Discriminating typical and atypical cystic fibrosis‐related bacteria by multiplex PNA‐FISH

Lopes

Carvalho

Azevedo

2016

Biotech & Bioengineering

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This study aims to report the development of peptide nucleic acid (PNA) probes to specifically detect the cystic fibrosis (CF)-associated traditional and atypical species Pseudomonas aeruginosa and Inquilinus limosus, respectively. PNA probes were designed in silico, developed and tested in smears prepared in phosphate-buffer saline (PBS), and in artificial sputum medium (ASM). A multiplex fluorescent in situ hybridization (FISH) approach using the designed probes was further validated in artificially contaminated clinical sputum samples and also applied in polymicrobial 24 h-old biofilms involving P. aeruginosa, I. limosus, and other CF-related bacteria. Both probes showed high predictive and experimental specificities and sensitivities. The multiplex PNA-FISH assay, associated with non-specific staining, was successfully adapted in the clinical samples and in biofilms of CF-related bacteria, allowing differentiating the community members and inferring about microbial-microbial interactions within the consortia. This study revealed the great potential of PNA-FISH as a diagnostic tool to discriminate between classical and less common CF-associated bacteria, being suitable to further describe species-dependent prevention strategies and deliver more effective target control therapeutics. Biotechnol. Bioeng. 2017;114: 355-367. © 2016 Wiley Periodicals, Inc.

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Cystic Fibrosis Therapy: A Community Ecology Perspective

Cited by 96 publications

References 59 publications

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

Six wedges to curing disease

Discriminating typical and atypical cystic fibrosis‐related bacteria by multiplex PNA‐FISH

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