Eur Respir J. 2022 Oct 20:2102861. doi: 10.1183/13993003.02861-2021. Online ahead of print.

ABSTRACT

BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions, and relationships to clinical outcome changes.

METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3-, 6-, 9, and 12-months post-ETI in 56 PWCF and compared to non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.

RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function, and localization to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens, and efferocytosis of apoptotic neutrophils was partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased FEV1 (+10%) and BMI (+1.0) showed fluctuations over time and were highly individualized. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride.

CONCLUSIONS: ETI is associated with unique changes in innate immune function and clinical outcomes.

PMID:36265882 | DOI:10.1183/13993003.02861-2021

Biomed Pharmacother. 2022 Oct 17;156:113886. doi: 10.1016/j.biopha.2022.113886. Online ahead of print.

ABSTRACT

Stop mutations cause 11% of the genetic diseases, due to the introduction of a premature termination codon (PTC) in the mRNA, followed by the production of a truncated protein. A promising therapeutic approach is the suppression therapy by Translational Readthrough Inducing Drugs (TRIDs), restoring the expression of the protein. Recently, three new TRIDs (NV848, NV914, NV930) have been proposed, and validated by several in vitro assays, for the rescue of the CFTR protein, involved in Cystic Fibrosis disease. In this work, an acute toxicological study for the three TRIDs was conducted in vivo on mice, according to the OECD No.420 guidelines. Animals were divided into groups and treated with a single dose of TRIDs molecules or Ataluren, an FDA-approved TRID molecule, as control. Mice were observed continuously for the first day post-drugs administration and the behavioral changes were recorded. On the 15th day, animals were sacrificed for histological examinations. The results showed that acute administration of 2000 mg/kg of NV914 and Ataluren and 300 mg/kg of NV848 or NV930, did not induce any mortality within 14 days. Moreover, histopathological analysis of treated mice showed no differences when compared to the experimental controls. In summary, our results suggest a good tolerability for the three molecules, and include NV848 and NV930 in a category 4 and NV914 in a category 5 of the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals, classifying these compounds in a low-risk scale for health.

PMID:36265311 | DOI:10.1016/j.biopha.2022.113886

PLoS One. 2022 Oct 20;17(10):e0276397. doi: 10.1371/journal.pone.0276397. eCollection 2022.

ABSTRACT

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in pancreatic ductal fluid secretion by mediating Cl- and HCO3- ion transport across the apical membrane. Severe CFTR mutations that diminish chloride conductance cause cystic fibrosis (CF) if both alleles are affected, whereas heterozygous carrier status increases risk for chronic pancreatitis (CP). It has been proposed that a subset of CFTR variants characterized by a selective bicarbonate conductance defect (CFTRBD) may be associated with CP but not CF. However, a rigorous genetic analysis of the presumed association has been lacking.

AIMS: To investigate the role of heterozygous CFTRBD variants in CP by meta-analysis of published case-control studies.

MATERIALS AND METHODS: A systematic search was conducted in the MEDLINE, Embase, Scopus, and CENTRAL databases for published studies that reported the CFTRBD variants p.R74Q, p.R75Q, p.R117H, p.R170H, p.L967S, p.L997F, p.D1152H, p.S1235R, and p.D1270N in CP patients and controls.

RESULTS: Twenty-two studies were eligible for quantitative synthesis. Combined analysis of the 9 CFTRBD variants indicated enrichment in CP patients versus controls (OR = 2.31, 95% CI = 1.17-4.56). Individual analysis of CFTRBD variants revealed no association of p.R75Q with CP (OR = 1.12, 95% CI = 0.89-1.40), whereas variants p.R117H and p.L967S were significantly overrepresented in cases relative to controls (OR = 3.16, 95% CI = 1.94-5.14, and OR = 3.88, 95% CI = 1.32-11.47, respectively). The remaining 6 low-frequency variants gave inconclusive results when analyzed individually, however, their pooled analysis indicated association with CP (OR = 2.08, 95% CI = 1.38-3.13).

CONCLUSION: Heterozygous CFTRBD variants, with the exception of p.R75Q, increase CP risk about 2-4-fold.

PMID:36264955 | DOI:10.1371/journal.pone.0276397

Science. 2022 Oct 21;378(6617):284-290. doi: 10.1126/science.ade2216. Epub 2022 Oct 20.

ABSTRACT

The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function.

PMID:36264792 | DOI:10.1126/science.ade2216

Drugs. 2022 Oct 20. doi: 10.1007/s40265-022-01785-1. Online ahead of print.

ABSTRACT

Due to their potent anti-inflammatory capacity (particularly in predominantly eosinophilic inflammation) and immunosuppressive properties, inhaled corticosteroids (ICSs) are widely used in asthmatic patients and also in individuals with chronic obstructive pulmonary disease (COPD) who suffer multiple exacerbations or have peripheral eosinophilia. However, there is little evidence for their use in non-cystic fibrosis bronchiectasis (hereafter, bronchiectasis). According to data extracted from large databases of bronchiectasis in adults, ICSs are used in more than 50% of patients without any scientific evidence to justify their efficacy and contrary to the recommendations of international guidelines on bronchiectasis that generally advise against their use. Indeed, bronchiectasis is a disease with predominantly neutrophilic inflammation and a high likelihood of chronic bacterial bronchial infection. Furthermore, it is known that due to their immunosuppressive properties, ICSs can induce an increase in bacterial infections. This manuscript aims to review the basic properties of ICSs, how they impact bronchiectasis in adults, the current position of international guidelines on this treatment, and the current indications and future challenges related to ICS use in bronchiectasis.

PMID:36264441 | DOI:10.1007/s40265-022-01785-1

Ann Med. 2022 Dec;54(1):2796-2804. doi: 10.1080/07853890.2022.2131282.

ABSTRACT

BACKGROUND: Notable emergence of multidrug-resistant bacteria has become increasingly problematic worldwide. Most patients with cystic fibrosis (CF) suffer from chronic persistent infections with frequent occurrence of acute exacerbations. Routine screening of bacterial strains, epidemiological characteristics, and resistance patterns are particularly useful for patient management and maintenance of infection control procedures.

METHODS: In this study, 43 pharyngeal samples were taken from patients with CF. Microbiological bacterial culture and identification, antimicrobial susceptibility testings, biofilm formation, including minimum biofilm eradication concentration (MBEC) and PCR for detecting resistance genes were performed.

RESULTS: All samples were positive for bacterial growth. The predominant species were Staphylococcus aureus (41.86%; n = 18) and Pseudomonas aeruginosa (39.53%; n = 17). 30% of isolated bacteria were multidrug-resistant, resisting high concentrations of tested antibiotics. Among the 42 biofilm-forming isolates, 23.8% (n = 10) were strong biofilm formers. The occurance of resistance genes varied with blaKPC detected in 71% (n = 17) of all Gram-negative isolates and mecA found in 61% (n = 11) of all S. aureus strains.

CONCLUSIONS: The majority of isolated bacteria were S. aureus and P. aeruginosa. The high frequency of antimicrobial resistance, the presence of resistance genes, and biofilm formation highlight the challenge in treatment and infection control measures in patients with CF.KEY MESSAGESStaphylococcus aureus and Pseudomonas aeruginosa are the most prevalent pathogens found in patients with CF in Jordan.Detection of antimicrobial resistance genes in patients with CF confirms that antimicrobial resistance patterns must always be monitored.Biofilm formation significantly increases the tolerance of bacteria to antimicrobial agents.

PMID:36264155 | DOI:10.1080/07853890.2022.2131282

ACS Med Chem Lett. 2022 Sep 6;13(10):1552-1553. doi: 10.1021/acsmedchemlett.2c00406. eCollection 2022 Oct 13.

ABSTRACT

Provided herein are novel substituted cyclopropyl compounds as CFTR modulators, pharmaceutical compositions, use of such compounds in treating cystic fibrosis, and processes for preparing such compounds.

PMID:36262401 | PMC:PMC9575177 | DOI:10.1021/acsmedchemlett.2c00406

Int J Mycobacteriol. 2022 Jul-Sep;11(3):303-308. doi: 10.4103/ijmy.ijmy_120_22.

ABSTRACT

BACKGROUND: Nontuberculous mycobacteria (NTMs) have now emerged as important opportunistic bacterial pathogens, particularly among patients with cystic fibrosis (CF). The development of improved molecular technologies and bioinformatics and the adoption of whole-genome sequencing to more isolates have allowed for a reanalysis of the existing taxa within the genus Mycobacterium, resulting in the renaming of some existing NTM Mycobacterium species to three novel genera, viz., Mycolicibacterium gen. nov., Mycolicibacter gen. nov. and Mycobacteroides gen. nov. This has resulted in controversy, particularly within the clinical community, accompanied by a reluctance to adopt and employ these new bacterial names. Therefore, the aims of this study were (i) to identify NTM organisms associated with CF lung disease that have been reported previously in the published literature, (ii) to examine the realignment of NTM organisms previously described in CF within the revised new mycobacterial taxonomy and renaming, and (iii) to identify and explore online taxonomical tools to help educate clinical medicine about recent changes in NTM taxonomy.

METHODS: Three tasks were performed, namely (i) to identify NTM organisms previously associated with people with CF, (ii) to examine the extent and scope of the reclassification of CF-related NTM species affected by changes in recent taxonomy and nomenclature, and (iii) to identify and examine the educational utility of online taxonomical educational tools/software (LifeMap [http://lifemap.univ-lyon1.fr/]; National Center for Biotechnology Information [NCBI] Taxonomy browser [https://www.ncbi.nlm.nih. gov/guide/taxonomy/]; and List of Prokaryotic names with Standing in Nomenclature [LPSN] [https://lpsn.dsmz.de/]). Mycobacterium (Mycobacteroides) abscessus was selected as the species to evaluate the application of these tools.

RESULTS: Twenty-one NTM species have been reported that have been associated with CF lung disease. Of these, two have been reclassified into the Mycobacteroides genus, two into the Mycolicibacter genus, and seven into the Mycolicibacterium genus. LifeMap, NCBI Taxonomy browser, and LPSN offered interactive visual support to better understand the taxonomy and nomenclature of NTM organisms.

CONCLUSION: We, therefore, advocate that clinical and scientific parties employ these online tools to gain a better insight into the familiarization and understanding of such evolving NTM classification, thereby aiding a better lexicon and communication among all stakeholders.

PMID:36260450 | DOI:10.4103/ijmy.ijmy_120_22

Int J Mycobacteriol. 2022 Jul-Sep;11(3):256-260. doi: 10.4103/ijmy.ijmy_87_22.

ABSTRACT

BACKGROUND: Members of the Mycobacterium abscessus complex have now emerged as clinically significant respiratory pathogens in people with cystic fibrosis (CF), potentially leading to increased disease severity, antibiotic treatment, and persistence dilemmas. Many of these species are resistant to disinfectants and biocides commonly used to clean and disinfect the hospital environment, thus necessitating the need to examine innovative ways to eliminate these organisms from such environments. It was, therefore, the aim of this study to examine the individual effect of ultraviolet-c (UVc) light (λ = 254 nm) and ozone (O3) on the growth of the M. abscessus complex organisms, as well as on seven other clinically significant CF pathogens, including Achromobacter spp., Burkholderia gladioli, Burkholderia cenocepacia, Burkholderia multivorans, Pseudomonas aeruginosa, Staphylococcus aureus, and Stenotrophomonas maltophilia.

METHODS: Bacterial isolates (n = 46), including M. abscessus complex (n = 6) (M. abscessus subsp abscessus [n = 2], M. abscessus subsp. bolletii [n = 2], M. abscessus subsp. massiliense [n = 2]), and other CF pathogens (n = 40) including Achromobacter spp., B. gladioli, B. cenocepacia, B. multivorans, P. aeruginosa, S. aureus, and S. maltophilia, were exposed for 1 h to UVc light (254 nm), as well as to ozone (O3; 26 ppm).

RESULTS: UVc light inactivated all M. abscessus complex organisms (n = 6), as well as the 40 isolates from the other genera and species. No bacterial species tested was able to survive the UVc treatment. O3 was unable to inactivate all isolates of M. abscessus subsp. abscessus (n = 2), M. abscessus subsp. bolletii (n = 2), and one isolate of M. abscessus subsp. massiliense, but killed one strain of M. abscessus subsp. massiliense. Overall, O3 inactivated only 20% of total isolates, allowing the posttreatment growth of the remaining 80% of isolates. There was no difference in the growth dynamic of P. aeruginosa from the environmental waters which had received O3 treatment and the control (untreated with O3). Bacterial growth, while occurring post-O3 treatment, was not as prolific in all remaining organisms, as in the untreated controls, demonstrating some but limited antibacterial effect.

CONCLUSIONS: From the data presented by this study, UVc light at 254 nm was effective at eliminating all organisms examined, including members of the M. abscessus complex. Given the refractory nature of these organisms against conventional wet chemical disinfection, UVc potentially offers a physical method to control and eliminate the survival of these organisms on health-care surfaces and fomites. For many CF species examined in this study, these data represent the first reports of the organisms susceptibility to UVc light. Further work is now required to establish time/distance parameters incorporated into newly designed innovative devices, to allow disinfection protocols to be optimized, and delivered to exploit this vulnerability with these nontuberculous mycobacterial organisms, as well as with the other bacterial species examined.

PMID:36260443 | DOI:10.4103/ijmy.ijmy_87_22

Asian J Androl. 2022 Oct 18. doi: 10.4103/aja202275. Online ahead of print.

ABSTRACT

Nonobstructive azoospermia (NOA) is a severe condition in infertile men, and increasing numbers of causative genes have been identified during the last few decades. Although certain causative genes can explain the presence of NOA in some patients, a proportion of NOA patients remain to be addressed. This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing. Whole-exome sequencing was performed in 46 male patients diagnosed with NOA. First, screening was performed for 119 genes known to be related to male infertility. Next, further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls. Finally, risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed. The frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls. Potential risk genes that may be causes of NOA were identified, including seven genes that were highly/specifically expressed in the testes. Four risk genes previously reported to be involved in spermatogenesis (MutS homolog 5 [MSH5], cilia- and flagella-associated protein 54 [CFAP54], MAP7 domain containing 3 [MAP7D3], and coiled-coil domain containing 33 [CCDC33]) and three novel risk genes (coiled-coil domain containing 168 [CCDC168], chromosome 16 open reading frame 96 [C16orf96], and serine protease 48 [PRSS48]) were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls. This study on clinical NOA patients provides further evidence for the four previously reported risk genes. The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.

PMID:36259570 | DOI:10.4103/aja202275

Cell J. 2022 Oct 1;24(10):596-602. doi: 10.22074/cellj.2022.8408.

ABSTRACT

OBJECTIVE: The most common mutation in cystic fibrosis (CF), (ΔF508-CFTR), results in impaired protein maturation, folding and transportation to the surface of the cell. As a consequence of impaired protein maturation and/or transport from the extracellular matrix to the cell, different systems are influenced, including gastrointestinal system and glandular system, reproductive system and respiratory systems. CF models are essential tools to provide further knowledge of CF pathophysiology. With this aim, we designed a transgenic CF model based on the homologous recombination (HR) system.

MATERIALS AND METHODS: In this experimental study, a specifically designed construct containing the CFTR gene with F508del was cloned into a PTZ57R cloning vector and then the construct was transformed into the male pronucleus by microinjection after in vitro fertilization (IVF). Then the rates of blastocyst formation and embryonic development at 72 hours after IVF, were evaluated using the inverted microscope and the insertion of the construct was approved by polymerase chain reaction (PCR) method.

RESULTS: The CFTR gene was successfully cloned into the PTZ57R cloning vector and overall, from 22 injected cells, 5 blastocysts were observed after pronuclear injection of the CFTR gene construct. PCR verification of the blastocyst with CFTR-specific primers represented complete recombination of CFTR into the mouse genome.

CONCLUSION: For the first time we designed a unique genome construction that can be detected using a simple PCR method. The pronuclear injection was performed for the transformation of the genome construct into the male pronuclei using microinjection and the development of zygote to the blastocyst stage has been observed following transgenesis.

PMID:36259477 | DOI:10.22074/cellj.2022.8408

Tanaffos. 2022 Jan;21(1):63-69.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a hereditary disease with a high mortality rate. The present study aimed to determine the effect of a physical activity program (PAP) on the life quality of children with CF at school age.

MATERIALS AND METHODS: This study conducted on 70 children with CF, the samples were randomly divided into intervention and control groups. A demographic information questionnaire and the Pediatric Quality of Life Inventory were used for data collection. This study was conducted in three stages and 2 months after the last intervention. Finally, the data were analyzed in SPSS software version 22 using the Chi-square test, independent t-test, and paired t-test at a p-value of less than 0.05.

RESULTS: The results indicated that the two groups had no significant difference in terms of demographic variables before the intervention. Moreover, it was observed that the mean scores of life quality in the physical, emotional, social, and academic performance of children in both groups before the intervention in child and parent evaluations did not show significant differences. After the intervention in the experimental group, the mean scores of life quality in all aspects significantly increased, compared to those of the control group (P<0.001). Moreover, there were no significant differences between the mean scores of life quality in the control group before and after the intervention.

CONCLUSION: Given the effectiveness of the intervention to enhance life quality, PAP is feasible and possible in the field of CF. It has to be noted that this method is an effective way to improve life quality.

PMID:36258917 | PMC:PMC9571229

Tanaffos. 2022 Jan;21(1):31-44.

ABSTRACT

BACKGROUND: It is widely accepted that concerns have been recently raised regarding the impact of air pollution on the health of children with cystic fibrosis (CF). Air pollution probably affects the exacerbation of CF and its laboratory findings. On the other hand, the World Health Organization (WHO) has asked all countries to update their data and reports on the distribution and prevalence of CF in different areas. The purpose of the present study was to investigate the distribution and prevalence of CF based on the levels of atmospheric pollutants, such as PM10, PM2.5, SO2, NO2, CO, and O3 in 22 zones of Tehran, and to report the abnormal laboratory findings that might indicate the exacerbation of CF.

MATERIALS AND METHODS: The studied statistical population included children with CF referred to Masih Daneshvari Hospital from 2003 to 2020. Demographic data, location of living area, and laboratory findings were extracted from patient records. The geographic information system (GIS) was applied to indicate the distribution and dispersion of the disease. The information related to air pollutants was collected from all stations in Tehran during the studied period by the Department of Environment of Tehran Province, and the average levels were used for final reporting.

RESULTS: The analysis results on 287 CF patients demonstrated that the risk of disease exacerbation significantly increased by the presence of air pollutants. In areas with multiple air pollutants, more laboratory findings were observed to be abnormal, and the lower survival rate for patients with CF was recorded. Investigating the CF distribution pattern based on climatic layers and above mean sea level (AMSL) indicated that distribution of the disease was higher in dry areas with lower AMSL and the higher volume of the atmospheric pollutants, which were primarily centralized in southern and central Tehran.

CONCLUSION: Environmental factors, such as air pollution, can be considered vital parameters, along with high-risk factors, such as pure and integrated race, migration, and mutation, influencing the prevalence and exacerbation of CF symptoms. Considering the higher prevalence of CF in deprived areas of Tehran, households' cultural and economic level appears to be a factor in the lack of diagnostic screening and prevention of CF in these areas. On the other hand, continuous monitoring of the air pollution caused by traffic and giving warnings to CF patients and their parents is particularly important.

PMID:36258909 | PMC:PMC9571236

Indian J Thorac Cardiovasc Surg. 2022 Nov;38(6):663-665. doi: 10.1007/s12055-022-01392-5. Epub 2022 Aug 1.

ABSTRACT

Allergic bronchopulmonary aspergillosis is usually seen in patients with asthma or cystic fibrosis. Its association with rheumatic heart disease has not been adequately reported in literature. We report our experience of three cases who were diagnosed cases of rheumatic heart disease. Their symptomatology and clinical findings required further evaluation and investigations, which were suggestive of allergic bronchopulmonary aspergillosis. The patients were treated with steroids and/or antifungals before proceeding with the valve replacement.

PMID:36258820 | PMC:PMC9569282 | DOI:10.1007/s12055-022-01392-5

Respir Res. 2022 Oct 18;23(1):288. doi: 10.1186/s12931-022-02202-7.

ABSTRACT

BACKGROUND: Although cardiovascular comorbidities negatively impact survival in patients with bronchiectasis, there is limited evidence to recommend exercise in this population. We aimed to evaluate whether exercise habit changes are related to reduced cardiovascular disease risk and explore an optimal exercise amount.

METHODS: This study identified 165,842 patients with newly diagnosed bronchiectasis during 2010-2016 who underwent two health examinations and were followed up until December 2020. The exposure was the change in weekly habits of moderate- or vigorous-intensity physical activity between the two examinations, classified into non-exercisers and exercisers (further classified into new exercisers, exercise dropouts, and exercise maintainers). The amount of exercise was measured using metabolic equivalents of task (MET). The outcome was the incidence of myocardial infarction (MI) or stroke.

RESULTS: During a mean of 6.2 ± 2.1 follow-up years, 4,233 (2.6%) and 3,745 (2.3%) of patients with bronchiectasis had MI or stroke, respectively. Compared to non-exercisers, exercisers had a significantly lower risk of MI or stroke by 9-28% (p < 0.001 for both). Among exercisers, exercise maintainers showed the lowest risk of MI (adjusted hazard ratio [aHR], 0.72; 95% confidence interval [CI], 0.64-0.81) and stroke (aHR, 0.72; 95% CI, 0.64-0.82) compared to non-exercisers. Regarding exercise amount, a significant risk reduction was observed only in patients with bronchiectasis who exercised for ≥ 500 MET-min/wk.

CONCLUSION: Exercise was associated with a reduced risk of cardiovascular diseases in patients with bronchiectasis. In particular, the risk was lowest in exercise maintainers, and cardiovascular risk reduction was significant when exercising more than 500 MET-min/wk.

PMID:36258193 | DOI:10.1186/s12931-022-02202-7

Adv Exp Med Biol. 2022;1386:397-424. doi: 10.1007/978-3-031-08491-1_15.

ABSTRACT

The human pathogens Pseudomonas aeruginosa and Staphylococcus aureus are frequently co-isolated from chronic wounds or cystic fibrosis patient airways. Clinical studies analysing the impact of co-infection on patient clinical outcomes lead to contradictory results. However, laboratory approaches suggest that the two pathogens co-colonize the same infection niches and form a mixed-species biofilm, therefore favouring their resistance to antibiotics and immune response. In parallel, many recent studies have focused on the different interactions between the two bacterial species. It has long been recognized that P. aeruginosa usually outcompetes S. aureus, and the molecular mechanisms involved in this state of bacterial competition are now well understood. However, several recent studies show that interactions between P. aeruginosa and S. aureus can be diverse and evolve over time. Thus, many CF isolates of P. aeruginosa and S. aureus can coexist and develop cooperative behaviours. In this chapter, we will provide an overview of the current knowledge on the mixed populations of P. aeruginosa and S. aureus, from their mechanisms of establishment to their impacts on bacterial physiology and clinical outcomes.

PMID:36258081 | DOI:10.1007/978-3-031-08491-1_15

Adv Exp Med Biol. 2022;1386:347-369. doi: 10.1007/978-3-031-08491-1_13.

ABSTRACT

Cystic fibrosis is a common genetically inherited, multisystem disorder caused by loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an apically situated anion channel. In the lung, lack of CFTR leads to airway surface dehydration, mucociliary clearance failure and an acidic pH in which innate defence molecules are rendered ineffective. Infection occurs early in life, with P. aeruginosa dominating by adolescence. The characteristic features of the CF airway highlighted above encourage persistence of infection, but P. aeruginosa also possess an array of mechanisms with which they attack host defences and render themselves protected from antimicrobials. Early eradication is usually successful, but this is usually transient. Chronic infection is manifest by biofilm formation which is resistant to treatment. Outcomes for people with CF have improved greatly in the last few decades, but particularly so with the recent advent of small molecule CFTR modulators. However, despite impressive efficacy on lung function and exacerbation frequency, most people with chronic infection remain with their pathogens. There is an active pipeline of new treatments including anti-biofilm and anti-quorum sensing molecules and non-drug approaches such as bacteriophage. Studies are reviewed and challenges for future drug development considered.

PMID:36258079 | DOI:10.1007/978-3-031-08491-1_13

Adv Exp Med Biol. 2022;1386:283-301. doi: 10.1007/978-3-031-08491-1_10.

ABSTRACT

Pseudomonas aeruginosa is classified as an opportunistic pathogen that causes a wide range of infections in humans, involving nearly all body systems, that vary from local to systemic and from self-limiting to life-threatening. This chapter outlines the features that have made P. aeruginosa a human pathogen. Each section starts with the argument in the heading followed by the epidemiological and/or experimental supportive evidence.

PMID:36258076 | DOI:10.1007/978-3-031-08491-1_10

Adv Exp Med Biol. 2022;1386:257-280. doi: 10.1007/978-3-031-08491-1_9.

ABSTRACT

The Pseudomonas aeruginosa type III secretion system (T3SS) is a complex molecular machine that delivers toxic proteins from the bacterial cytoplasm directly into host cells. This apparatus spans the inner and outer membrane and employs a needle-like structure that penetrates through the eucaryotic cell membrane into the host cell cytosol. The expression of the P. aeruginosa T3SS is highly regulated by environmental signals including low calcium and host cell contact. P. aeruginosa strains with mutations in T3SS genes are less pathogenic, suggesting that the T3SS is a virulence mechanism. Given that P. aeruginosa is naturally antibiotic resistant and multidrug resistant isolates are rapidly emerging, new antibiotics to target P. aeruginosa are needed. Furthermore, even if new antibiotics were to be developed, the timeline between when an antibiotic is released and resistance development is relatively short. Therefore, the concept of targeting virulence factors has garnered attention. So-called "antivirulence" approaches do not kill the microbe but instead focus on rendering it harmless and therefore unable to cause damage. Since these therapies target a particular system or pathway, the normal microbiome is unlikely to be affected and there is less concern about the spread to other microbes. Finally, and most importantly, since any antivirulence drug does not kill the microbe, there should be less selective pressure to develop resistance to these inhibitors. The P. aeruginosa T3SS has been well studied due to its importance for pathogenesis in numerous human and animal infections. Thus, many P. aeruginosa T3SS inhibitors have been described as potential antivirulence therapeutics, some of which have progressed to clinical trials.

PMID:36258075 | DOI:10.1007/978-3-031-08491-1_9

Adv Exp Med Biol. 2022;1386:147-184. doi: 10.1007/978-3-031-08491-1_6.

ABSTRACT

Bacteria sense their environment via the cell envelope, which in Gram-negative bacteria comprises the outer membrane, the periplasmic space, and the inner membrane. Pseudomonas aeruginosa is an opportunistic pathogen which is exposed to different cell wall stresses imposed by exposure to antibiotics, osmotic pressure, and long-time colonization of host tissues such as the lung in cystic fibrosis patients. In response to these stresses, P. aeruginosa is able to respond by establishing a cell envelope stress response involving different regulatory pathways including the extra-cytoplasmic sigma factors AlgU, SigX, and SbrI and other two-component sensor/response regulators and effectors. This chapter aims to review the different factors leading to the activation of the cell envelope stress response in P. aeruginosa and the genetic determinants involved in this response, which is crucial for the survival of the bacterium upon exposure to different stressful conditions.

PMID:36258072 | DOI:10.1007/978-3-031-08491-1_6