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Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections.

ABSTRACT: Repeated cycles of infections, caused mainly by Pseudomonas aeruginosa, combined with a robust host immune response and tissue injury, determine the course and outcome of cystic fibrosis (CF) lung disease. As the disease progresses, P. aeruginosa adapts to the host modifying dramatically its phenotype; however, it remains unclear whether and how bacterial adaptive variants and their persistence influence the pathogenesis and disease development. Using in vitro and murine models of infection, we showed that P. aeruginosa CF-adaptive variants shaped the innate immune response favoring their persistence. Next, we refined a murine model of chronic pneumonia extending P. aeruginosa infection up to three months. In this model, including CFTR-deficient mice, we unveil that the P. aeruginosa persistence lead to CF hallmarks of airway remodelling and fibrosis, including epithelial hyperplasia and structure degeneration, goblet cell metaplasia, collagen deposition, elastin degradation and several additional markers of tissue damage. This murine model of P. aeruginosa chronic infection, reproducing CF lung pathology, will be instrumental to identify novel molecular targets and test newly tailored molecules inhibiting chronic inflammation and tissue damage processes in pre-clinical studies.

SUBMITTER: Cigana C

PROVIDER: S-EPMC4756310 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections.

Cigana Cristina C Lorè Nicola Ivan NI Riva Camilla C De Fino Ida I Spagnuolo Lorenza L Sipione Barbara B Rossi Giacomo G Nonis Alessandro A Cabrini Giulio G Bragonzi Alessandra A

Scientific reports 20160217

Repeated cycles of infections, caused mainly by Pseudomonas aeruginosa, combined with a robust host immune response and tissue injury, determine the course and outcome of cystic fibrosis (CF) lung disease. As the disease progresses, P. aeruginosa adapts to the host modifying dramatically its phenotype; however, it remains unclear whether and how bacterial adaptive variants and their persistence influence the pathogenesis and disease development. Using in vitro and murine models of infection, we ...[more]

PMID: 26883959

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Project description:UnlabelledAdaptation of bacterial pathogens to a host can lead to the selection and accumulation of specific mutations in their genomes with profound effects on the overall physiology and virulence of the organisms. The opportunistic pathogen Pseudomonas aeruginosa is capable of colonizing the respiratory tract of individuals with cystic fibrosis (CF), where it undergoes evolution to optimize survival as a persistent chronic human colonizer. The transcriptome of a host-adapted, alginate-overproducing isolate from a CF patient was determined following growth of the bacteria in the presence of human respiratory mucus. This stable mucoid strain responded to a number of regulatory inputs from the mucus, resulting in an unexpected repression of alginate production. Mucus in the medium also induced the production of catalases and additional peroxide-detoxifying enzymes and caused reorganization of pathways of energy generation. A specific antibacterial type VI secretion system was also induced in mucus-grown cells. Finally, a group of small regulatory RNAs was identified and a fraction of these were mucus regulated. This report provides a snapshot of responses in a pathogen adapted to a human host through assimilation of regulatory signals from tissues, optimizing its long-term survival potential.ImportanceThe basis for chronic colonization of patients with cystic fibrosis (CF) by the opportunistic pathogen Pseudomonas aeruginosa continues to represent a challenging problem for basic scientists and clinicians. In this study, the host-adapted, alginate-overproducing Pseudomonas aeruginosa 2192 strain was used to assess the changes in its transcript levels following growth in respiratory CF mucus. Several significant and unexpected discoveries were made: (i) although the alginate overproduction in strain 2192 was caused by a stable mutation, a mucus-derived signal caused reduction in the transcript levels of alginate biosynthetic genes; (ii) mucus activated the expression of the type VI secretion system, a mechanism for killing of other bacteria in a mixed population; (iii) expression of a number of genes involved in respiration was altered; and (iv) several small regulatory RNAs were identified, some being mucus regulated. This work highlights the strong influence of the host environment in shaping bacterial survival strategies.

Project description:Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

Project description:Chronic biofilm infections by Pseudomonas aeruginosa are a major contributor to the morbidity and mortality of patients. The formation of multicellular bacterial aggregates, called biofilms, is associated with increased resistance to antimicrobials and immune clearance and the persistence of infections. Biofilm formation is dependent on bacterial cell attachment to surfaces, and therefore, attachment plays a key role in chronic infections. We hypothesized that bacteria sense various surfaces and initiate a rapid, specific response to increase adhesion and establish biofilms. RNA sequencing (RNA-Seq) analysis identified transcriptional changes of adherent cells during initial attachment, identifying the bacterial response to an abiotic surface over a 1-h period. Subsequent screens investigating the most highly regulated genes in surface attachment identified 4 genes, pfpI, phnA, leuD, and moaE, all of which have roles in both metabolism and biofilm formation. In addition, the transcriptional responses to several different medically relevant abiotic surfaces were compared after initial attachment. Surprisingly, there was a specific transcriptional response to each surface, with very few genes being regulated in response to surfaces in general. We identified a set of 20 genes that were differentially expressed across all three surfaces, many of which have metabolic functions, including molybdopterin cofactor biosynthesis and nitrogen metabolism. This study has advanced the understanding of the kinetics and specificity of bacterial transcriptional responses to surfaces and suggests that metabolic cues are important signals during the transition from a planktonic to a biofilm lifestyle. IMPORTANCE Bacterial biofilms are a significant concern in many aspects of life, including chronic infections of airways, wounds, and indwelling medical devices; biofouling of industrial surfaces relevant for food production and marine surfaces; and nosocomial infections. The effects of understanding surface adhesion could impact many areas of life. This study utilized emerging technology in a novel approach to address a key step in bacterial biofilm development. These findings have elucidated both conserved and surface-specific responses to several disease-relevant abiotic surfaces. Future work will expand on this report to identify mechanisms of biofilm initiation with the aim of identifying bacterial factors that could be targeted to prevent biofilms.

Dataset Information

Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections.

Publications

Tracking the immunopathological response to Pseudomonas aeruginosa during respiratory infections.

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