scholarly journals The Yin and Yang ofStreptococcusLung Infections in Cystic Fibrosis: a Model for Studying Polymicrobial Interactions

2019 ◽  
Vol 201 (11) ◽  
Author(s):  
Jessie E. Scott ◽  
George A. O’Toole
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Microbial Interactions ◽  
Oral Streptococci ◽  
Content Type ◽  
Lung Microbiome ◽  
Oral Microflora ◽  
Streptococcus Milleri ◽  
Yin And Yang

ABSTRACTThe streptococci are increasingly recognized as a core component of the cystic fibrosis (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The presence of theStreptococcus millerigroup (SMG; also known as the anginosus group streptococci [AGS]) correlates with exacerbation when these microbes are the predominant species in the lung. In contrast, microbiome studies have indicated that an increased relative abundance of streptococci in the lung, including members of the oral microflora, correlates with impacts on lung disease less severe than those caused by other CF-associated microflora, indicating a complex role for this genus in the context of CF. Recent findings suggest that streptococci in the CF lung microenvironment may influence the growth and/or virulence of other CF pathogens, as evidenced by increased virulence factor production byPseudomonas aeruginosawhen grown in coculture with oral streptococci. Conversely, the presence ofP. aeruginosacan enhance the growth of streptococci, including members of the SMG, a phenomenon that could be exacerbated by the fact that streptococci are not susceptible to some of the frontline antibiotics used to treatP. aeruginosainfections. Collectively, these studies indicate the necessity for further investigation into the role of streptococci in the CF airway to determine how these microbes, alone or via interactions with other CF-associated pathogens, might influence CF lung disease, for better or for worse. We also propose that the interactions of streptococci with other CF pathogens is an ideal model to study clinically relevant microbial interactions.

scholarly journals Microbial Interactions in the Cystic Fibrosis Airway

2018 ◽  
Vol 56 (8) ◽  
Author(s):  
Ann M. Granchelli ◽  
Frederick R. Adler ◽  
Ruth H. Keogh ◽  
Christiana Kartsonaki ◽  
David R. Cox ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Burkholderia Cepacia ◽  
Patient Characteristics ◽  
Microbial Interactions ◽  
Achromobacter Xylosoxidans ◽  
Content Type ◽  
Negatively Associated ◽  
Logistic Regression Models ◽  
Multiple Observations

ABSTRACT Interactions in the airway ecology of cystic fibrosis may alter organism persistence and clinical outcomes. Better understanding of such interactions could guide clinical decisions. We used generalized estimating equations to fit logistic regression models to longitudinal 2-year patient cohorts in the Cystic Fibrosis Foundation Patient Registry, 2003 to 2011, in order to study associations between the airway organisms present in each calendar year and their presence in the subsequent year. Models were adjusted for clinical characteristics and multiple observations per patient. Adjusted models were tested for sensitivity to cystic fibrosis-specific treatments. The study included 28,042 patients aged 6 years and older from 257 accredited U.S. care centers and affiliates. These patients had produced sputum specimens for at least two consecutive years that were cultured for methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Candida and Aspergillus species. We analyzed 99.8% of 538,458 sputum cultures from the patients during the study period. Methicillin-sensitive S. aureus was negatively associated with subsequent P. aeruginosa. P. aeruginosa was negatively associated with subsequent B. cepacia complex, A. xylosoxidans, and S. maltophilia. B. cepacia complex was negatively associated with the future presence of all bacteria studied, as well as with that of Aspergillus species. P. aeruginosa, B. cepacia complex, and S. maltophilia were each reciprocally and positively associated with Aspergillus species. Independently of patient characteristics, the organisms studied interact and alter the outcomes of treatment decisions, sometimes in unexpected ways. By inhibiting P. aeruginosa, methicillin-sensitive S. aureus may delay lung disease progression. P. aeruginosa and B. cepacia complex may inhibit other organisms by decreasing airway biodiversity, potentially worsening lung disease.

scholarly journals Pseudomonas aeruginosa Can Inhibit Growth of Streptococcal Species via Siderophore Production

2019 ◽  
Vol 201 (8) ◽  
Author(s):  
Jessie E. Scott ◽  
Kewei Li ◽  
Laura M. Filkins ◽  
Bin Zhu ◽  
Sherry L. Kuchma ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Response To Treatment ◽  
Oral Streptococci ◽  
Interspecies Interactions ◽  
Viridans Streptococci ◽  
Content Type ◽  
Streptococcus Milleri ◽  
Polymicrobial Infections

ABSTRACT Cystic fibrosis (CF) is a genetic disease that causes patients to accumulate thick, dehydrated mucus in the lung and develop chronic, polymicrobial infections due to reduced mucociliary clearance. These chronic polymicrobial infections and subsequent decline in lung function are significant factors in the morbidity and mortality of CF. Pseudomonas aeruginosa and Streptococcus spp. are among the most prevalent organisms in the CF lung; the presence of P. aeruginosa correlates with lung function decline, and the Streptococcus milleri group (SMG), a subgroup of the viridans streptococci, is associated with exacerbations in patients with CF. Here we characterized the interspecies interactions that occur between these two genera. We demonstrated that multiple P. aeruginosa laboratory strains and clinical CF isolates promote the growth of multiple SMG strains and oral streptococci in an in vitro coculture system. We investigated the mechanism by which P. aeruginosa enhances growth of streptococci by screening for mutants of P. aeruginosa PA14 that are unable to enhance Streptococcus growth, and we identified the P. aeruginosa pqsL::TnM mutant, which failed to promote growth of Streptococcus constellatus and S. sanguinis. Characterization of the P. aeruginosa ΔpqsL mutant revealed that this strain cannot promote Streptococcus growth. Our genetic data and growth studies support a model whereby the P. aeruginosa ΔpqsL mutant overproduces siderophores and thus likely outcompetes Streptococcus sanguinis for limited iron. We propose a model whereby competition for iron represents one important means of interaction between P. aeruginosa and Streptococcus spp. IMPORTANCE Cystic fibrosis (CF) lung infections are increasingly recognized for their polymicrobial nature. These polymicrobial infections may alter the biology of the organisms involved in CF-related infections, leading to changes in growth, virulence, and/or antibiotic tolerance, and could thereby affect patient health and response to treatment. In this study, we demonstrate interactions between P. aeruginosa and streptococci using a coculture model and show that one interaction between these microbes is likely competition for iron. Thus, these data indicate that one CF pathogen may influence the growth of another, and they add to our limited knowledge of polymicrobial interactions in the CF airway.

scholarly journals 2045 The role of TGFβ in driving early cystic fibrosis lung disease

2018 ◽  
Vol 2 (S1) ◽  
pp. 33-33
Author(s):  
Elizabeth L. Kramer ◽  
William Hardie ◽  
Kristin Hudock ◽  
Cynthia Davidson ◽  
Alicia Ostmann ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Genetic Modifier ◽  
Lavage Fluid ◽  
Lung Mechanics ◽  
Patient Specific

OBJECTIVES/SPECIFIC AIMS: Transforming growth factor-beta (TGFβ) is a genetic modifier of cystic fibrosis (CF) lung disease. TGFβ’s pulmonary levels in young CF patients and its mechanism of action in CF are unknown. We examined TGFβ levels in children with CF and investigated responses of human airway epithelial cells (AECs) and mice to TGFβ. METHODS/STUDY POPULATION: TGFβ levels in bronchoalveolar lavage fluid from CF patients (n=15) and non-CF control patients (n=21)<6 years old were determined by ELISA. CF mice and non-CF mice were intratracheally treated with an adenoviral TGFβ1 vector or PBS; lungs were collected for analysis at day 7. Human CF and non-CF AECs were treated with TGFβ or PBS for 24 hours then collected for analysis. RESULTS/ANTICIPATED RESULTS: Young CF patients had higher bronchoalveolar lavage fluid TGFβ than non-CF controls (p=0.03). Mouse lungs exposed to TGFβ demonstrated inflammation, goblet cell hyperplasia, and decreased CFTR expression. CF mice had greater TGFβ-induced lung mechanics abnormalities than controls; both CF human AECs and CF mice showed higher TGFβ induced MAPK and PI3K signaling compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: For the first time, we show increased TGFβ levels very early in CF. TGFβ drives CF lung abnormalities in mouse and human models; CF models are more sensitive to TGFβ’s effects. Understanding the role of TGFβ in promoting CF lung disease is critical to developing patient specific treatments.

scholarly journals Posaconazole therapy in children with cystic fibrosis and Aspergillus-related lung disease

2019 ◽  
Vol 58 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Deepa Patel ◽  
Sarah Popple ◽  
Alison Claydon ◽  
Deborah E Modha ◽  
Erol A Gaillard
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Plasma Levels ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Tablet Formulation ◽  
Full Blood Count ◽  
Systemic Corticosteroids ◽  
Liquid Preparation ◽  
A Prospective Study

Abstract There is emerging evidence for the role of posaconazole in the management of Aspergillus-related cystic fibrosis (CF) lung disease. The tolerability and efficacy of posaconazole in paediatric CF is not well established. We report a prospective study over a fifty-three month period evaluating the safety, tolerability, and efficacy of posaconazole in pediatric CF. Fourteen children (seven males, median age 13 years, range 3–17 years) received a total of twenty-three courses of posaconazole (13 oral suspension and 10 tablet formulation). Of these patient episodes, nine received posaconazole for emerging or active allergic bronchopulmonary aspergillosis (ABPA) and two required a combination of posaconazole and systemic corticosteroids for difficult-to-treat ABPA. A subgroup of patients (n = 12) with persistent isolates of Aspergillus fumigatus, in the absence of serological markers of ABPA, received posaconazole monotherapy for pulmonary exacerbations not responding to conventional broad-spectrum antibiotic treatment. Posaconazole levels, full blood count, electrolytes, and liver function were monitored on day 7 of treatment and then monthly. Posaconazole was well tolerated in all but three patients. Therapeutic plasma levels &gt;1 mg/l were achieved in all receiving the tablet formulation in comparison to 60% on the liquid preparation. There was a modest but significant improvement in FEV1 (% predicted) demonstrated for the cohort as a whole (p = 0.015) following posaconazole therapy. Posaconazole is well tolerated in children as young as six years old, improvements in lung function are observed, and therapeutic plasma levels are readily achieved in patients taking the tablet formulation and in adherent patients taking the liquid formulation.

scholarly journals The yin and yang nature of coopetition activities: non-linear effects and the moderating role of competitive intensity for internationalised firms

2020 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
James M. Crick ◽  
Dave Crick
Keyword(s):  
Chinese Philosophy ◽  
Market Performance ◽  
Company Performance ◽  
Competitive Intensity ◽  
Content Type ◽  
Non Linear ◽  
Yin And Yang ◽  
The Impact ◽  
Moderating Role

PurposeThis paper draws upon the Yin and Yang concept of Chinese philosophy within a Western context to examine coopetition, namely, the interplay between cooperation and competition. Although coopetition activities should positively affect company performance, earlier research involving this relationship has typically been linear in nature and without moderating factors. Consequently, underpinned by resource-based theory and the relational view, the purpose of this investigation is to examine the non-linear (inverted U-shaped) link between coopetition and company performance under the moderating role of competitive intensity.Design/methodology/approachCollection of survey data involved a sample of 101 internationalising wine producers in New Zealand. Following a check of the statistical data for all major assessments of reliability and validity (together with common method variance), testing the research hypotheses and control paths took place through hierarchical regression. Furthermore, 20 semi-structured interviews helped explain the underlying mechanisms behind the quantitative results.FindingsCoopetition had a non-linear (inverted U-shaped) relationship with market performance. Surprisingly, competitive intensity yielded a negative moderation effect. The mixed methods results highlighted that firms must strike an effective balance between the paradoxical forces of cooperativeness and competitiveness across their product-market strategies.Originality/valueThis investigation contributes to the existing literature by developing and testing a conceptual framework examining the nature of the relationship between coopetition activities and market performance – using non-linear (inverted U-shaped) and moderating effects. It addresses a debate between two schools-of-thought concerning the impact of competitive intensity on the coopetition paradox. Additionally, this study helps to explain the coopetition construct through the Yin and Yang concept to highlight how the paradoxical forces of cooperativeness and competitiveness can create harmful outcomes for organisations if they do not manage them effectively (across domestic and international markets).

Neutrophils in cystic fibrosis

2016 ◽  
Vol 397 (6) ◽  
pp. 485-496 ◽  
Author(s):  
Julie Laval ◽  
Anjali Ralhan ◽  
Dominik Hartl
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Structural Damage ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Current Evidence ◽  
Infection And Inflammation ◽  
Shed Light

Abstract Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

scholarly journals The CFTR and ENaC debate: how important is ENaC in CF lung disease?

2012 ◽  
Vol 302 (11) ◽  
pp. L1141-L1146 ◽  
Author(s):  
James F. Collawn ◽  
Ahmed Lazrak ◽  
Zsuzsa Bebok ◽  
Sadis Matalon
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ongoing Debate ◽  
The Subject ◽  
Cystic Fibrosis Transmembrane ◽  
Epithelial Sodium Channel Enac

Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease.

scholarly journals PmrB Mutations Promote Polymyxin Resistance of Pseudomonas aeruginosa Isolated from Colistin-Treated Cystic Fibrosis Patients

2011 ◽  
Vol 56 (2) ◽  
pp. 1019-1030 ◽  
Author(s):  
Samuel M. Moskowitz ◽  
Mark K. Brannon ◽  
Nandini Dasgupta ◽  
Miyuki Pier ◽  
Nicole Sgambati ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lipid A ◽  
Clinical Isolates ◽  
Gain Of Function ◽  
Content Type ◽  
Regulatory Systems ◽  
Repeated Passage ◽  
High Level

ABSTRACTPseudomonas aeruginosacan develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance,P. aeruginosaisolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-functionpmrBalleles that conferred polymyxin resistance to strains with a wild-type orpmrABdeletion background. Double mutantpmrBalleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutantpmrBalleles induced transcription from the promoter of thearnBoperon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate thatpmrBgain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains ofP. aeruginosa.

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