Thorax. 2021 Oct 25:thoraxjnl-2020-215185. doi: 10.1136/thoraxjnl-2020-215185. Online ahead of print.

ABSTRACT

INTRODUCTION: Inhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we introduce a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) capable of providing safe, widespread and robust transgene expression in in vivo and in vitro models of muco-obstructive lung diseases.

METHODS: We investigated the ability of DNA-MPP to mediate reporter and/or therapeutic transgene expression in lung airways of a transgenic mouse model of muco-obstructive lung diseases (ie, Scnn1b-Tg) and in air-liquid interface cultures of primary human bronchial epithelial cells harvested from an individual with cystic fibrosis. A plasmid designed to silence epithelial sodium channel (ENaC) hyperactivity, which causes airway surface dehydration and mucus stasis, was intratracheally administered via DNA-MPP to evaluate therapeutic effects in vivo with or without pretreatment with hypertonic saline, a clinically used mucus-rehydrating agent.

RESULTS: DNA-MPP exhibited marked greater reporter transgene expression compared with a mucus-impermeable formulation in in vivo and in vitro models of muco-obstructive lung diseases. DNA-MPP carrying ENaC-silencing plasmids provided efficient downregulation of ENaC and reduction of mucus burden in the lungs of Scnn1b-Tg mice, and synergistic impacts on both gene transfer efficacy and therapeutic effects were achieved when DNA-MPP was adjuvanted with hypertonic saline.

DISCUSSION: DNA-MPP constitutes one of the rare gene delivery systems providing therapeutically meaningful gene transfer efficacy in highly relevant in vivo and in vitro models of muco-obstructive lung diseases due to its unique ability to efficiently penetrate airway mucus.

PMID:34697091 | DOI:10.1136/thoraxjnl-2020-215185

PLoS One. 2021 Oct 25;16(10):e0258950. doi: 10.1371/journal.pone.0258950. eCollection 2021.

ABSTRACT

Biofilm infections are hard to manage using conventional antibiotic treatment regimens because biofilm structures discourage antibiotics from reaching the entire bacterial community and allow pathogen cells to persistently colonize and develop a plethora of tolerance mechanisms towards antibiotics. Moreover, the dispersed cells from biofilms can cause further complications by colonizing different sites and establishing new cycles of biofilms. Previously, we showed that alginate lyase enzyme (AlyP1400), purified from a marine Pseudoalteromonas bacterium, reduced Pseudomonas aeruginosa biofilm biomass and boosted bactericidal activity of tobramycin by degrading alginate within the biofilm extracellular polymeric substances matrix. In this work, we used a flow cytometry-based assay to analyze collected dispersal cells and demonstrated the synergy between tobramycin with AlyP1400 in enhancing the release of both live and dead biofilm cells from a mucoid P. aeruginosa strain CF27, which is a clinical isolate from cystic fibrosis (CF) patients. Interestingly, this enhanced dispersal was only observed when AlyP1400 was combined with tobramycin and administered simultaneously but not when AlyP1400 was added in advance of tobramycin in a sequential manner. Moreover, neither the combined nor sequential treatment altered the dispersal of the biofilms from a non-mucoid P. aeruginosa laboratory strain PAK. We then carried out the gene expression and tobramycin survival analyses to further characterize the impacts of the combined treatment on the CF27 dispersal cells. Gene expression analysis indicated that CF27 dispersal cells had increased expression in virulence- and antibiotic resistance-related genes, including algR, bdlA, lasB, mexF, mexY, and ndvB. In the CF27 dispersal cell population, the combinational treatment of AlyP1400 with tobramycin further induced bdlA, mexF, mexY, and ndvB genes more than non-treated and tobramycin-treated dispersal cells, suggesting an exacerbated bacterial stress response to the combinational treatment. Simultaneous to the gene expression analysis, the survival ability of the same batch of biofilm dispersal cells to a subsequent tobramycin challenge displayed a significantly higher tobramycin tolerant fraction of cells (~60%) upon the combinational treatment of AlyP1400 and tobramycin than non-treated and tobramycin-treated dispersal cells, as well as the planktonic cells (all below 10%). These results generate new knowledge about the gene expression and antibiotic resistance profiles of dispersed cells from biofilm. This information can guide the design of safer and more efficient therapeutic strategies for the combinational use of alginate lyase and tobramycin to treat P. aeruginosa biofilm-related infections in CF lungs.

PMID:34695148 | DOI:10.1371/journal.pone.0258950

J Pediatr Gastroenterol Nutr. 2021 Oct 21. doi: 10.1097/MPG.0000000000003335. Online ahead of print.

ABSTRACT

OBJECTIVES: Adult studies suggest that patients with isolated colonic Crohn's disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2.

METHODS: Retrospective data was collected through the Porto IBD group of ESPGHAN on paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to 1st flare, hospital admissions, initiation of anti-TNFα drug, stricture and surgery.

RESULTS: Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of ASCA and pANCA positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to 1st flare and admission were similar between groups, patients with L1 were commenced on anti-TNFα earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2.

CONCLUSIONS: Significant differences are observed in the clinical presentation and outcomes of paediatric patients with L2, compared to patients with L1 and UC.

PMID:34694270 | DOI:10.1097/MPG.0000000000003335

Cochrane Database Syst Rev. 2021 Jul 20;7:CD013196. doi: 10.1002/14651858.CD013196.pub2.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD, including bronchitis and emphysema) is a chronic condition causing shortness of breath, cough, and exacerbations leading to poor health outcomes. Face-to-face visits with health professionals can be hindered by severity of COPD or frailty, and by people living at a distance from their healthcare provider and having limited access to services. Telehealth technologies aimed at providing health care remotely through monitoring and consultations could help to improve health outcomes of people with COPD.

OBJECTIVES: To assess the effectiveness of telehealth interventions that allow remote monitoring and consultation and multi-component interventions for reducing exacerbations and improving quality of life, while reducing dyspnoea symptoms, hospital service utilisation, and death among people with COPD.

SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register. Additional sources searched included the US National Institutes of Health Ongoing Trials Register, the World Health Organization International Clinical Trials Registry Platform, and the IEEEX Xplore Digital Library. The latest search was conducted in April 2020. We used the GRADE approach to judge the certainty of evidence for outcomes.

SELECTION CRITERIA: Eligible randomised controlled trials (RCTs) included adults with diagnosed COPD. Asthma, cystic fibrosis, bronchiectasis, and other respiratory conditions were excluded. Interventions included remote monitoring or consultation plus usual care, remote monitoring or consultation alone, and mult-component interventions from all care settings. Quality of life scales included St George's Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). The dyspnoea symptom scale used was the Chronic Respiratory Disease Questionnaire Self-Administered Standardized Scale (CRQ-SAS).

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed confidence in the evidence for each primary outcome using the GRADE method. Primary outcomes were exacerbations, quality of life, dyspnoea symptoms, hospital service utilisation, and mortality; a secondary outcome consisted of adverse events.

MAIN RESULTS: We included 29 studies in the review (5654 participants; male proportion 36% to 96%; female proportion 4% to 61%). Most remote monitoring interventions required participants to transfer measurements using a remote device and later health professional review (asynchronous). Only five interventions transferred data and allowed review by health professionals in real time (synchronous). Studies were at high risk of bias due to lack of blinding, and certainty of evidence ranged from moderate to very low. We found no evidence on comparison of remote consultations with or without usual care. Remote monitoring plus usual care (8 studies, 1033 participants) Very uncertain evidence suggests that remote monitoring plus usual care may have little to no effect on the number of people experiencing exacerbations at 26 weeks or 52 weeks. There may be little to no difference in effect on quality of life (SGRQ) at 26 weeks (very low to low certainty) or on hospitalisation (all-cause or COPD-related; very low certainty). COPD-related hospital re-admissions are probably reduced at 26 weeks (hazard ratio 0.42, 95% confidence interval (CI) 0.19 to 0.93; 106 participants; moderate certainty). There may be little to no difference in deaths between intervention and usual care (very low certainty). We found no evidence for dyspnoea symptoms or adverse events. Remote monitoring alone (10 studies, 2456 participants) Very uncertain evidence suggests that remote monitoring may result in little to no effect on the number of people experiencing exacerbations at 41 weeks (odds ratio 1.02, 95% CI 0.67 to 1.55). There may be little to no effect on quality of life (SGRQ total at 17 weeks, or CAT at 38 and 52 weeks; very low certainty). There may be little to no effect on dyspnoea symptoms on the CRQ-SAS at 26 weeks (low certainty). There may be no difference in effects on the number of people admitted to hospital (very low certainty) or on deaths (very low certainty). We found no evidence for adverse events. Multi-component interventions with remote monitoring or consultation component (11 studies, 2165 participants) Very uncertain evidence suggests that multi-component interventions may have little to no effect on the number of people experiencing exacerbations at 52 weeks. Quality of life at 13 weeks may improve as seen in SGRQ total score (mean difference -9.70, 95% CI -18.32 to -1.08; 38 participants; low certainty) but not at 26 or 52 weeks (very low certainty). COPD assessment test (CAT) scores may improve at a mean of 38 weeks, but evidence is very uncertain and interventions are varied. There may be little to no effect on the number of people admitted to hospital at 33 weeks (low certainty). Multi-component interventions are likely to result in fewer people re-admitted to hospital at a mean of 39 weeks (OR 0.50, 95% CI 0.31 to 0.81; 344 participants, 3 studies; moderate certainty). There may be little to no difference in death at a mean of 40 weeks (very low certainty). There may be little to no effect on people experiencing adverse events (very low certainty). We found no evidence for dyspnoea symptoms.

AUTHORS' CONCLUSIONS: Remote monitoring plus usual care provided asynchronously may not be beneficial overall compared to usual care alone. Some benefit is seen in reduction of COPD-related hospital re-admissions, but moderate-certainty evidence is based on one study. We have not found any evidence for dyspnoea symptoms nor harms, and there is no difference in fatalities when remote monitoring is provided in addition to usual care. Remote monitoring interventions alone are no better than usual care overall for health outcomes. Multi-component interventions with asynchronous remote monitoring are no better than usual care but may provide short-term benefit for quality of life and may result in fewer re-admissions to hospital for any cause. We are uncertain whether remote monitoring is responsible for the positive impact on re-admissions, and we are unable to discern the long-term benefits of receiving remote monitoring as part of patient care. Owing to paucity of evidence, it is unclear which COPD severity subgroups would benefit from telehealth interventions. Given there is no evidence of harm, telehealth interventions may be beneficial as an additional health resource depending on individual needs based on professional assessment. Larger studies can determine long-term effects of these interventions.

PMID:34693988 | DOI:10.1002/14651858.CD013196.pub2

Front Cell Infect Microbiol. 2021 Oct 8;11:760922. doi: 10.3389/fcimb.2021.760922. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease affecting more than 70,000 people worldwide. It is caused by a mutation in the cftr gene, a chloride ion transporter localized in the plasma membrane of lung epithelial cells and other organs. The loss of CFTR function alters chloride, bicarbonate, and water transport through the plasma membrane, promoting the production of a thick and sticky mucus in which bacteria including Pseudomonas aeruginosa and Burkholderia cenocepacia can produce chronic infections that eventually decrease the lung function and increase the risk of mortality. Autophagy is a well-conserved lysosomal degradation pathway that mediates pathogen clearance and plays an important role in the control of bacterial infections. In this mini-review, we describe the principal strategies used by P. aeruginosa and B. cenocepacia to survive and avoid microbicidal mechanisms within the autophagic pathway leading to the establishment of chronic inflammatory immune responses that gradually compromise the lung function and the life of CF patients.

PMID:34692569 | PMC:PMC8531276 | DOI:10.3389/fcimb.2021.760922

ISME J. 2021 Oct 23. doi: 10.1038/s41396-021-01129-z. Online ahead of print.

ABSTRACT

Bacterial infection and inflammation of the airways are the leading causes of morbidity and mortality in persons with cystic fibrosis (CF). The ecology of the bacterial communities inhabiting CF airways is poorly understood, especially with respect to how community structure, dynamics, and microbial metabolic activity relate to clinical outcomes. In this study, the bacterial communities in 818 sputum samples from 109 persons with CF were analyzed by sequencing bacterial 16S rRNA gene amplicons. We identified eight alternative community types (pulmotypes) by using a Dirichlet multinomial mixture model and studied their temporal dynamics in the cohort. Across patients, the pulmotypes displayed chronological patterns in the transition among each other. Furthermore, significant correlations between pulmotypes and patient clinical status were detected by using multinomial mixed effects models, principal components regression, and statistical testing. Constructing pulmotype-specific metabolic activity profiles, we found that pulmotype microbiota drive distinct community functions including mucus degradation or increased acid production. These results indicate that pulmotypes are the result of ordered, underlying drivers such as predominant metabolism, ecological competition, and niche construction and can form the basis for quantitative, predictive models supporting clinical treatment decisions.

PMID:34689185 | DOI:10.1038/s41396-021-01129-z

Arch Biochem Biophys. 2021 Oct 21:109062. doi: 10.1016/j.abb.2021.109062. Online ahead of print.

ABSTRACT

Bacterial biofilms are an alternative lifestyle in which communities of bacteria are embedded in an extracellular matrix manly composed by polysaccharides, nucleic acids and proteins, being the hallmark of bacterial survival in a variety of ecological niches. Amyloid fibrils are one of the proteinaceous components of such extracellular crowded environments. FapC is the main component of the functional amyloid recently discovered in Pseudomonas species, including the opportunistic pathogen P. aeruginosa, which is a major cause of nosocomial infections and contamination of medical devices. Considering that several functional roles have been attributed to this bacterial amyloid, FapC emerged as a novel target to control Pseudomonas biofilm formation and to design new treatments against chronic infections. In this study, we used complementary biophysical techniques to evaluate conformational signatures of FapC amyloids formed in the presence of alginate, the major exopolysaccharide associated with the mucoid phenotype of P. aeruginosa strains isolated from cystic fibrosis patients. We found that the this naturally occurring macromolecular crowder leads to morphological similar yet polymorphic FapC fibrils, highlighting the importance of considering the complexity of the extracellular matrix in order to improve our understanding of microbial functional amyloids.

PMID:34688606 | DOI:10.1016/j.abb.2021.109062

J Cyst Fibros. 2021 Oct 20:S1569-1993(21)01421-1. doi: 10.1016/j.jcf.2021.09.016. Online ahead of print.

NO ABSTRACT

PMID:34688556 | DOI:10.1016/j.jcf.2021.09.016

Lancet Respir Med. 2021 Oct 21:S2213-2600(21)00458-6. doi: 10.1016/S2213-2600(21)00458-6. Online ahead of print.

NO ABSTRACT

PMID:34688435 | DOI:10.1016/S2213-2600(21)00458-6

Pediatr Transplant. 2021 Oct 23:e14165. doi: 10.1111/petr.14165. Online ahead of print.

ABSTRACT

BACKGROUND: Asymptomatic pulmonary nodules may appear at any point after lung transplantation. The differential diagnosis is broad and includes serious life-threatening disease entities.

METHODS: A retrospective case report of a single patient who developed a pulmonary nodule after lung transplantation.

RESULTS: At 2 years post-transplant, an 11-year-old with cystic fibrosis was asymptomatic and had normal lung function. A single nodule was noted on surveillance chest CT scan. Initial evaluation was negative, but subsequently, he was diagnosed with cryptococcal osteomyelitis in a thoracic rib. He responded well to an extended course of antifungal therapy without loss of allograft function or infectious complications.

CONCLUSION: Pulmonary nodules after lung transplantation may be a harbinger of serious complications. A systematic approach to evaluation and follow-up is recommended.

PMID:34687575 | DOI:10.1111/petr.14165

Lett Appl Microbiol. 2021 Oct 23. doi: 10.1111/lam.13589. Online ahead of print.

ABSTRACT

Broth microdilution assays were used to determine minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indices (FICIs) of tea tree oil (TTO), tobramycin, colistin, and aztreonam against clinical cystic fibrosis-associated P. aeruginosa (CFPA) isolates (n=20). The minimum biofilm eradication concentration (MBEC) and fractional biofilm eradication concentration index (FBECI) were also determined using a similar microbroth dilution checkerboard assay, with biofilms formed using the MBEC device®. TTO was effective at lower concentrations against multi-drug resistant (MDR) CFPA isolates (n=3) in a biofilm compared to in a planktonic state (MBEC 18.7-fold lower than MIC). CFPA within biofilm was less susceptible to aztreonam, colistin and tobramycin compared to planktonic cells (MBEC 6.3-fold, 9.3-fold, and 2.1-fold higher than MIC, respectively). All combinations of essential oil and antibiotic showed indifferent relationships (FICI 0.52 - 1.72) when tested against planktonic MDR CFPA isolates (n=5). Against CFPA isolates (n=3) in biofilm, combinations of TTO/aztreonam and TTO/colistin showed indifferent relationships (mean FBECI 0.85 and 0.60, respectively), whereas TTO/tobramycin showed a synergistic relationship (mean FBECI 0.42). The antibiofilm properties of TTO and the synergistic relationship seen between TTO and tobramycin against CFPA in vitro make inhaled TTO a promising candidate as a potential therapeutic agent.

PMID:34687564 | DOI:10.1111/lam.13589

Pediatr Pulmonol. 2021 Oct 23. doi: 10.1002/ppul.25740. Online ahead of print.

ABSTRACT

OBJECTIVES: Inhaled recombinant human deoxyribonuclease (dornase alfa) and osmotic agents such as inhaled mannitol are used for improving the clearance of secretions of cystic fibrosis (CF) patients. We aimed to evaluate the long term clinical effects of adding dry powder inhaled (DPI) mannitol in subjects with CF who are taking daily dornase alfa.

METHOD: We conducted a retrospective case-control study on subjects with CF. The effect of DPI mannitol was assessed by comparing DPI mannitol and dornase alfa combination with daily dornase alfa alone in children with CF during a 12-month period. The primary outcome measures of the study were absolute changes in percent predicted forced expiratory volume in 1s (FEV1) and FEV1 z-scores and the secondary outcomes included other spirometry indices, body mass index, frequency of pulmonary exacerbations, SPO2, and sputum microbiology.

RESULT: Of a total of 28 patients who committed to use DPI mannitol treatments during the study period, 5 had a positive challenge with DPI mannitol and 2 were aged over 18 years. Therefore, the mannitol treatment group consisted of 21 patients. However, the effect of DPI mannitol was analyzed using 15 patients in the mannitol treatment group who received DPI mannitol for at least 12 months and 18 patients who only used dornase alfa constituted the control group. The median absolute change in FEV1 between baseline and the 3rd month; and baseline and the 12th month were significantly higher in the mannitol treatment group (p=0.038, p=0.004, resp.). When the groups are compared with respect to absolute z-score changes, all spirometry indices, except FVC at the end of 3 months, showed statistically significant improvements in the mannitol treatment group. Some secondary outcomes like pulmonary exacerbation frequency during the study year and median absolute BMI z-score changes from baseline to the end of the study showed no significant differences between the groups (p=0.735, p=0.161, resp.). No colonization changes were observed in the treatment group.

CONCLUSIONS: This study showed that in those patients who tolerated long term (12 months) treatment with DPI mannitol and dornase alfa made greater improvements in FEV1, FVC, FEV1/FVC, FEF25-75 z-scores than treatment with dornase alfa alone in children with CF. This article is protected by copyright. All rights reserved.

PMID:34687284 | DOI:10.1002/ppul.25740

Pediatr Pulmonol. 2021 Oct 23. doi: 10.1002/ppul.25741. Online ahead of print.

ABSTRACT

BACKGROUND: Individuals with cystic fibrosis (CF) and fungal airway infection may present with fungal bronchitis, allergic bronchopulmonary aspergillosis (ABPA) or may appear unaffected despite fungal detection. We sought to characterize people with CF with frequent detection of fungi from airway samples and determine clinical outcomes.

METHODS: This retrospective study included individuals with CF with ≥ 4 lower airway cultures over a 2-year baseline period and ≥ 2 years of follow-up. We defined two groups: ≤ 1 positive fungus culture (rare) or ≥ 2 positive cultures during baseline (frequent). Clinical characteristics and outcomes were determined.

RESULTS: Between 2004-2016, 294 individuals met inclusion with 62% classified as rare and 38% as frequent fungi during baseline. Median follow-up was 6 years (range 2-9 years). Aspergillus fumigatus was the most common fungal species detected. Individuals with frequent fungi were older (13.7 vs. 11.7 yrs, p = 0.02) and more likely to have Stenotrophomonas maltophilia (35% vs 17%, p < 0.001) at baseline, but did not differ in lung function or ABPA diagnosis. During follow-up, those with frequent fungi were more likely to have chronic P. aeruginosa and S. maltophilia. Individuals with ABPA and frequent fungi had the highest rates of co-infection and co-morbidities, and a trend towards more rapid lung function decline.

DISCUSSION: Fungal infection in CF was associated with frequent P. aeruginosa and S. maltophilia co-infection even in those without ABPA. Individuals with frequent fungi and ABPA had worse outcomes, highlighting the potential contribution of fungi to CF pulmonary disease. This article is protected by copyright. All rights reserved.

PMID:34687280 | DOI:10.1002/ppul.25741

Thorax. 2021 Oct 22:thoraxjnl-2021-218134. doi: 10.1136/thoraxjnl-2021-218134. Online ahead of print.

NO ABSTRACT

PMID:34686569 | DOI:10.1136/thoraxjnl-2021-218134

Paediatr Respir Rev. 2021 Sep 29:S1526-0542(21)00094-4. doi: 10.1016/j.prrv.2021.09.006. Online ahead of print.

ABSTRACT

Large gains have been made in the management of respiratory diseases associated with cystic fibrosis (CF). Initial studies evaluating sleep issues in CF focused on respiratory problems of nocturnal hypoxia, alveolar hypoventilation and risk of airway obstruction from nasal polyps with treatment evaluations including long term oxygen therapy or noninvasive ventilation in case of nocturnal hypercapnia. More recent studies include patients whose lung function is better preserved, and have permitted more focus on sleep patterns and sleep quality. This literature identified that reduced sleep duration and poor sleep quality are common and may be explained by chronic pain and cough, frequent stools, gastro-oesophageal reflux, nasal obstruction or sinusitis, and drugs such as corticosteroids or beta-agonists. In the teenage years, poor sleep hygiene, sleep debt and poor sleep quality are associated with depression, poor academic performance, less physical activity, and a decrease in quality of life. Restless leg syndrome also seems to be common in adult patients with CF. These sleep problems seem more important in patients with a low lung function but may also be observed in patients with preserved lung function. The consequences of poor sleep may potentially exaggerate the multi-organ morbidity of CF, such as pain, inflammation, susceptibility to infection, and glucose intolerance, but these aspects are largely under-evaluated. Sleep should be evaluated on a routine basis in CF and prospective studies assessing the benefits of interventions aiming at improving sleep duration and sleep quality urgently needed.

PMID:34686437 | DOI:10.1016/j.prrv.2021.09.006

Cell Rep. 2021 Oct 19;37(3):109829. doi: 10.1016/j.celrep.2021.109829.

ABSTRACT

Pseudomonas aeruginosa notoriously adapts to the airways of people with cystic fibrosis (CF), yet how infection-site biogeography and associated evolutionary processes vary as lifelong infections progress remains unclear. Here we test the hypothesis that early adaptations promoting aggregation influence evolutionary-genetic trajectories by examining longitudinal P. aeruginosa from the sinuses of six adults with CF. Highly host-adapted lineages harbored mutator genotypes displaying signatures of early genome degradation associated with recent host restriction. Using an advanced imaging technique (MiPACT-HCR [microbial identification after passive clarity technique]), we find population structure tracks with genome degradation, with the most host-adapted, genome-degraded P. aeruginosa (the mutators) residing in small, sparse aggregates. We propose that following initial adaptive evolution in larger populations under strong selection for aggregation, P. aeruginosa persists in small, fragmented populations that experience stronger effects of genetic drift. These conditions enrich for mutators and promote degenerative genome evolution. Our findings underscore the importance of infection-site biogeography to pathogen evolution.

PMID:34686349 | DOI:10.1016/j.celrep.2021.109829

Cells. 2021 Oct 19;10(10):2793. doi: 10.3390/cells10102793.

ABSTRACT

Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.

PMID:34685773 | PMC:PMC8534516 | DOI:10.3390/cells10102793

Materials (Basel). 2021 Oct 15;14(20):6117. doi: 10.3390/ma14206117.

ABSTRACT

Cystic fibrosis is an inherited disease that affects multiple organs and systems. The oral cavity can serve as a substantial source of bacteria, causing respiratory infections and diseases which continue to dictate the clinical course of the disease and prognosis in patients with CF. Low voltage and electric current could effectively kill bacteria and biofilms, and the activity of milliampere currents could be used as an effective method of fighting bacteria. This study evaluated the effect of low amperage electric current on the formation of Staphylococcus aureus biofilms on dental implants such as titanium and zirconium in patients with cystic fibrosis. Our studies suggest that a constant electric current at a low intensity of 1 mA and 10 mA is inhibiting bacterial adhesion, detaching biofilm-forming bacteria on biomaterials used in dental implants such as titanium and zirconium, and destroying bacterial cells of Staphylococcus aureus strains. In addition, we observed the selection of an appropriate biomaterial for implants in people affected by chronic diseases, such as CF, should be carefully planned.

PMID:34683710 | PMC:PMC8537792 | DOI:10.3390/ma14206117

Microorganisms. 2021 Oct 19;9(10):2172. doi: 10.3390/microorganisms9102172.

ABSTRACT

The adherence of Proteus mirabilis to the surface of urinary catheters leads to colonization and eventual blockage of the catheter lumen by unique crystalline biofilms produced by these opportunistic pathogens, making P. mirabilis one of the leading causes of catheter-associated urinary tract infections. The Proteus biofilms reduce efficiency of antibiotic-based treatment, which in turn increases the risk of antibiotic resistance development. Bacteriophages and their enzymes have recently become investigated as alternative treatment options. In this study, a novel Proteus bacteriophage (vB_PmiS_PM-CJR) was isolated from an environmental sample and fully characterized. The phage displayed depolymerase activity and the subsequent genome analysis revealed the presence of a pectate lyase domain in its tail spike protein. The protein was heterologously expressed and purified; the ability of the purified tail spike to degrade Proteus biofilms was tested. We showed that the application of the tail spike protein was able to reduce the adherence of bacterial biofilm to plastic pegs in a MBEC (minimum biofilm eradication concentration) assay and improve the survival of Galleria mellonella larvae infected with Proteus mirabilis. Our study is the first to successfully isolate and characterize a biofilm depolymerase from a Proteus phage, demonstrating the potential of this group of enzymes in treatment of Proteus infections.

PMID:34683494 | PMC:PMC8539402 | DOI:10.3390/microorganisms9102172

Microorganisms. 2021 Sep 26;9(10):2033. doi: 10.3390/microorganisms9102033.

ABSTRACT

Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

PMID:34683354 | PMC:PMC8537719 | DOI:10.3390/microorganisms9102033