J Cyst Fibros. 2021 Apr 5:S1569-1993(21)00102-8. doi: 10.1016/j.jcf.2021.03.020. Online ahead of print.

NO ABSTRACT

PMID:33832854 | DOI:10.1016/j.jcf.2021.03.020

Eur J Ophthalmol. 2021 Apr 8:11206721211008780. doi: 10.1177/11206721211008780. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is the most common life-shortening recessive genetic disease in Caucasians, affecting primarily the lungs. The objective of our study was to investigate potential ophthalmologic involvement in adult patients with CF.

METHODS: Fifty adult patients with cystic fibrosis and 60 age- and sex-matched controls underwent complete ophthalmologic examination including tear-film Break-Up Time (BUT), Macular Thickness, and peripapillary Retinal Nerve Fiber Layer (pRNFL) thickness measurements using Spectral Domain-OCT.

RESULTS: CF patients had significantly lower nasal-inferior pRNFL thickness (median 82 IQR 67-102 vs 92.5 IQR 82-107, p = 0.005) and lower percentage of normal tear Break-Up Time (56.0% vs 96.7%, p = 0.001) than healthy controls. All CF patients with BUT <10 s were diagnosed with blepharitis at the time of our assessement. The subgroup of patients homozygous for the most common CF mutation, F508del, had lower nasal-inferior pRNFL thickness (p = 0.014) and lower percentage of normal tear Break-Up Time (p = 0.001) compared to the control group. Additional findings, present in the CF group only, were punctuate retinal hemorrhages (four patients), vessel tortuosity (four patients), snail-track degeneration, and retinal tufts (two patients without refractive error). There were no significant differences in visual acuity, refractive errors, gonioscopic findings, or intraocular pressure between the groups.

CONCLUSIONS: Our study is, to the best of our knowledge, the largest ophthalmologic study of patients with cystic fibrosis. We found that CF patients had significantly decreased inferior-quadrant peripapillary retinal nerve fiber layer thickness and decreased tear-film break-up time compared to controls. We highlight the importance of careful regular ophthalmologic assessment and follow-up of these patients.

PMID:33832348 | DOI:10.1177/11206721211008780

Public Health. 2021 Apr 5;193:126-138. doi: 10.1016/j.puhe.2021.02.005. Online ahead of print.

ABSTRACT

OBJECTIVES: A systematic narrative literature review was undertaken to assess the acceptability of childhood screening interventions to identify factors to consider when planning or modifying childhood screening programs to maximize participation and uptake.

STUDY DESIGN: This is a systematic narrative literature review.

METHODS: Electronic databases were searched (MEDLINE, EMBASE, PsycINFO via Ovid, CINAHL, and Cochrane Library) to identify primary research studies that assessed screening acceptability. Studies were categorized using an existing theoretical framework of acceptability consisting of seven constructs: affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, and self-efficacy. A protocol was developed and registered with PROSPERO (registration no. CRD42018099763) RESULTS: The search identified 4529 studies, and 46 studies met the inclusion criteria. Most studies involved neonatal screening. Programs identified included newborn blood spot screening (n = 22), neonatal hearing screening (n = 13), Duchenne muscular dystrophy screening (n = 4), cystic fibrosis screening (n = 3), screening for congenital heart defects (n = 2), and others (n = 2). Most studies assessed more than one construct of acceptability. The most common constructs identified were affective attitude (how a parent feels about the program) and intervention coherence (parental understanding of the program, and/or the potential consequences of a confirmed diagnosis).

CONCLUSIONS: The main acceptability component identified related to parental knowledge and understanding of the screening process, the testing procedure(s), and consent. The emotional impact of childhood screening mostly explored maternal anxiety. Further studies are needed to examine the acceptability of childhood screening across the wider family unit. When planning new (or refining existing) childhood screening programs, it is important to assess acceptability before implementation. This should include assessment of important issues such as information needs, timing of information, and when and where the screening should occur.

PMID:33831694 | DOI:10.1016/j.puhe.2021.02.005

Am J Respir Cell Mol Biol. 2021 Apr 8. doi: 10.1165/rcmb.2021-0070ED. Online ahead of print.

NO ABSTRACT

PMID:33831321 | DOI:10.1165/rcmb.2021-0070ED

J Asthma. 2021 Apr 8:1-9. doi: 10.1080/02770903.2021.1914649. Online ahead of print.

ABSTRACT

ObjectiveAsthma is a heterogeneous disease consisting of several inflammatory phenotypes of which neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids. The development of targeted therapies requires the identification of biomarkers to distinguish these phenotypes. Currently, we lack validated biomarkers for non-eosinophilic asthma. The aim of this study is to examine serum calprotectin (SC) in asthmatics and its potential as biomarker for neutrophilic asthma.MethodsHundred-seventeen severe asthmatics were referred for sputum induction and data were obtained from their medical records. To evaluate the association between SC and asthma phenotypes, patients were divided into subgroups based on sputum cell count (3% eosinophils and 61% neutrophils). Additionally, SC levels of asthmatics were compared with these of patients with chronic obstructive pulmonary disease, non-cystic fibrosis bronchiectasis and healthy controls.ResultsAsthmatics (n = 45) had significantly higher levels of SC than healthy controls. No significant differences were found between the different asthma phenotypes and in comparison with COPD patients. SC was significantly higher in asthmatics with a lower FEV1/FVC ratio (< 70) and non-significantly elevated SC levels were seen in asthmatics with frequent exacerbations (> 2 in the last year).ConclusionIn conclusion, there was no difference in SC levels between the different inflammatory subtypes in asthmatics. Nevertheless, severe asthmatics seemed to have higher SC levels suggesting that SC may be a marker of disease severity rather than a marker for specific inflammatory subtypes in asthmatics. Further research in larger cohorts is necessary to validate SC as biomarker in severe asthmatics.

PMID:33830849 | DOI:10.1080/02770903.2021.1914649

Pediatr Pulmonol. 2021 Apr 8. doi: 10.1002/ppul.25409. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbations (PEx) are associated with a significant drop in pulmonary function. The clinical value of measuring bronchodilator (BD) responsiveness during treatment for PEx to monitor or predict recovery of lung function is unclear.

METHODS: A retrospective analysis of spirometry with BD response testing obtained during hospital admissions for PEx in pediatric CF patients. Repeated events were included for patients with BD testing during multiple admissions.

RESULTS: 249 spirometries with BD testing in 102 patients were completed around day 7 (day 4-10) of hospital admission for treatment of CF PEx. Median (IQR) forced expiratory volume in one second (FEV1 ) was 70.6% predicted (58.1, 84.6) prior to the PEx event (best FEV1 in 6 months prior to admission), 54.4% (41.5, 66.9) at admission, 62.3% (48.4, 74.7) around day 7 of admission and 67.1% predicted (53.8, 78.2) at end of treatment. BD response around day 7 correlated poorly with FEV1 prior to PEx (r=-0.16, p=0.02), and did not correlate with recovery to baseline FEV1 at end of treatment (r=0.08, p=0.22). Only 23/249 (9%) individual tests had a BD response in FEV1 of ≥12 % and 200 ml. BD response was not related to age or severity of lung disease and led to an immediate change in clinical management in only 4 cases.

CONCLUSIONS: Significant BD response in CF patients treated for PEx is rare, shows poor correlation with baseline pulmonary function and does not correlate with recovery of FEV1 with treatment. These data suggest that routine testing for BD response is not indicated during PEx. This article is protected by copyright. All rights reserved.

PMID:33830642 | DOI:10.1002/ppul.25409

Eur J Clin Microbiol Infect Dis. 2021 Apr 8. doi: 10.1007/s10096-021-04235-0. Online ahead of print.

ABSTRACT

A 26-year-old girl with a longstanding colonization by Pandoraea nosoerga underwent liver-lung transplantation for cystic fibrosis (CF) in 2018. Her brother also suffering from CF was also colonized by P. nosoerga. Despite appropriate perioperative antibiotic therapy, she had post-transplant bacteremic pneumonia caused by extensively drug-resistant P. nosoerga. Drug repurposing was used to optimize treatment options. The cause of post-transplant contamination was studied by comparative whole-genome sequencing including pre- and post-transplant strains and her brother's strains. Post-transplant contamination appeared to be due to her own pre-transplant strain, emphasizing the urgent need to study and implement effective decontamination protocols before transplantation.

PMID:33830365 | DOI:10.1007/s10096-021-04235-0

JCI Insight. 2021 Apr 8;6(7):140750. doi: 10.1172/jci.insight.140750.

ABSTRACT

Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.

PMID:33830084 | DOI:10.1172/jci.insight.140750

Mediators Inflamm. 2021 Mar 19;2021:6682657. doi: 10.1155/2021/6682657. eCollection 2021.

ABSTRACT

BACKGROUND: Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult βENaC-Tg mice with established disease.

METHODS: βENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS-/- βENaC-Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically.

RESULTS: At 6 weeks of age, βENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS-/- βENaC-Tg mice and βENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS-/- βENaC-Tg mice, therapeutic inhibition of CatS in βENaC-Tg mice had no effect on established emphysema-like lung tissue damage.

CONCLUSIONS: These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease.

PMID:33828414 | PMC:PMC8004367 | DOI:10.1155/2021/6682657

Clin Chem Lab Med. 2021 Apr 7. doi: 10.1515/cclm-2020-1661. Online ahead of print.

ABSTRACT

OBJECTIVES: Sweat chloride testing (SCT) is the mainstay for the diagnosis of cystic fibrosis (CF) and biomarker in the evaluation of CFTR-modifying drugs. To be a reliable and valid tool, analytical variance (CVA) must be minimized. However, external quality assessments have revealed significant deviations in routine clinical practice. Our goal was to identify and quantify technical errors through proficiency testing and simulations.

METHODS: Chloride concentrations of three blinded samples (each as triplicates) were measured in 9 CF centers using a chloridometer in a routine setting. Technical errors were simulated and quantified in a series of measurements. We compared imprecision and bias before and after a counseling session by evaluating coefficients of variation (CV), adherence to tolerance limits, and inter-rater variability coefficients.

RESULTS: Pipetting errors resulting in changes in sample volume were identified as the main source of error with deviations up to 41%. After the counseling session, the overall CVA decreased from 7.6 to 5.2%, the pass rate increased from 67 to 92%, and the inter-rater variability diminished. Significant deviations continued to be observed in individual centers.

CONCLUSIONS: Prevention of technical errors in SCT decreases imprecision and bias. Quality assurance programs must be established in all CF centers, including staff training, standard operating procedures, and proficiency testing.

PMID:33826811 | DOI:10.1515/cclm-2020-1661

PLoS One. 2021 Apr 7;16(4):e0249687. doi: 10.1371/journal.pone.0249687. eCollection 2021.

ABSTRACT

Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis, an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. In this study we highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among 9 fibrotic diseases. We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our Drug Repurposing results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven't been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis. We suggest digoxin to be tested against Oral Submucous Fibrosis, since we observe cardiomyopathy-related pathways implicated in Oral Submucous Fibrosis and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that Idiopathic Pulmonary Fibrosis shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren's Disease, IgG4-related Disease, Systemic Sclerosis and Cystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.

PMID:33826640 | DOI:10.1371/journal.pone.0249687

Per Med. 2021 Apr 7. doi: 10.2217/pme-2020-0161. Online ahead of print.

ABSTRACT

Aim: Organoid technology has enormous potential for precision medicine, such as has recently been demonstrated in the field of cystic fibrosis. However, storage and use of organoids has been associated with ethical challenges and there is currently a lack of harmony in regulation and guidelines to govern the rapid emergence of 'organoid medicine'. Developing sound governance demands incorporation of the perspectives of patients as key stakeholders. Materials & methods: We conducted 17 semi-structured interviews with people with cystic fibrosis to explore their perspectives on the ethics and governance of organoid biobanking. Results: We identified three themes: prioritization of research and trust, ambivalent views on commercial involvement and transparency and control. Conclusion: Our study offers important insights for ethically robust governance of 'organoid medicine'.

PMID:33825546 | DOI:10.2217/pme-2020-0161

Am J Physiol Lung Cell Mol Physiol. 2021 Apr 7. doi: 10.1152/ajplung.00082.2021. Online ahead of print.

ABSTRACT

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

PMID:33825507 | DOI:10.1152/ajplung.00082.2021

Indian J Pediatr. 2021 Apr 7. doi: 10.1007/s12098-021-03733-5. Online ahead of print.

NO ABSTRACT

PMID:33825131 | DOI:10.1007/s12098-021-03733-5

Pak J Pharm Sci. 2020 Sep;33(5):1933-1937.

ABSTRACT

Multi-specie infections display diverse interactions among pathogens that influence the severity of disease. Staphylococcus aureus and Pseudomonas aeruginosa are the two most important opportunistic, nosocomial and drug-resistant pathogens. Poly-infections due to S. aureus and P. aeruginosa are more destructive and result in worse patient outcome than mono-infection. The two organisms are commonly isolated from cystic fibrosis respiratory cultures. Studies demonstrated that S. aureus pre-colonization among cystic fibrosis patients is a hazardous for beginning P. aeruginosa aviation route infection. This work meant to explore the impact of P. aeruginosa on the destructiveness of S. aureus and the level of disease's seriousness by utilizing in-vitro co-culture and host cell model. The outcomes showed that P. aeruginosa outcompetes and suppresses the growth of S. aureus when co-cultured. The host factors expression profile indicated elevated expression of TNFα, IL-6 and IL-12, recommending the unique mechanism of host cell healing inhibition by multispecies. Co-infection resulted in significant increase in IL-8 together with the 10-fold induction of iNOS expression when contrast with S. aureus mono-infection. This indicates that the presence of P. aeruginosa heads the infection towards more severity and complications and delays cell healing process.

PMID:33824098

Expert Opin Drug Discov. 2021 Apr 6. doi: 10.1080/17460441.2021.1912732. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a life-threatening inherited disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel expressed at the apical membrane of secretory epithelia. CF leads to multiorgan dysfunction with progressive deterioration of lung function being the major cause of untimely death. Conventional CF therapies target only symptoms and consequences downstream of the primary genetic defect and the current life expectancy and quality of life of these individuals are still very limited.

AREA COVERED: CFTR modulator drugs are novel specialized therapies that enhance or even restore functional expression of CFTR mutants and have been approved for clinical use for individuals with specific CF genotypes. This review summarized classical approaches used for the pre-clinical development of CFTR correctors and potentiators as well as emerging strategies aiming to accelerate modulator development and expand theratyping efforts.

EXPERT OPINION: : Highly effective CFTR modulator drugs are expected to deeply modify the disease course for the majority of individuals with CF. A multitude of experimental approaches has been established to accelerate the development of novel modulators. CF patient-derived specimens are valuable cell models to predict therapeutic effectiveness of existing (and novel) modulators in a precision medicine approach.

PMID:33823716 | DOI:10.1080/17460441.2021.1912732

Thromb Haemost. 2021 Apr 6. doi: 10.1055/a-1475-2351. Online ahead of print.

ABSTRACT

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a Phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low molecular weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality (ACM) 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4x upper limit of normal (ULN) or sepsis-induced coagulopathy (SIC) score ≥4. Subjects are randomized to enoxaparin 1 mg/kg SQ/BID (CrCl ≥ 30 ml/min) or 0.5 mg/kg (CrCl 15-30 ml/min) vs local institutional prophylactic regimens including: a) UFH up to 22,500 IU daily (divided BID or TID), b) enoxaparin 30mg and 40mg SQ QD or BID, or c) dalteparin 2500IU or 5000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction (RRR) with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4x ULN, stratification by ICU vs non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.

PMID:33823560 | DOI:10.1055/a-1475-2351

Physiother Theory Pract. 2021 Apr 6:1-7. doi: 10.1080/09593985.2021.1904470. Online ahead of print.

ABSTRACT

Objectives: The Manchester Musculoskeletal Screening Tool (MMST) is used internationally to screen for pain, postural changes, and urinary incontinence in adults with cystic fibrosis (CF). The tool has been validated for the outcome measures of pain and incontinence but not for the thoracic movement section. The aim of this study was to assess intra (single rater) and inter-rater (between rater) reliability of the thoracic movement screen section of the MMST.Methods: This is a prospective reliability study. Digital videos of thoracic movement were taken of adults with CF during their annual musculoskeletal screening at a large UK Adult CF Center. Twelve physiotherapists independently watched the videos and scored the movements on two occasions, 2 weeks apart, using MMST. Cohen's kappa and Krippendorff alpha were used to establish intra- and inter-rater reliability.Results: Intra-rater reliability using Cohen's kappa calculation ranged between 0.35 and 0.93. Eleven out of 12 physiotherapists had a moderate-substantial reliability score as assessed by the Landis Koch criteria. Percentage agreement for each physiotherapist ranged from 67%-97%. The inter-rater reliability was poor (Krippendorff alpha score = 0.422 (CI: 0.24-0.60)).Conclusion: The thoracic section of the MMST is reliable in adults with CF to highlight changes in posture and thoracic mobility that may go undetected or under-reported by the patient when repeated by the same clinician. However, the inter-rater variability is high, and it should not be considered reliable when carried out by different clinicians over time.

PMID:33822675 | DOI:10.1080/09593985.2021.1904470

Pediatr Pulmonol. 2021 Apr 6. doi: 10.1002/ppul.25395. Online ahead of print.

ABSTRACT

Sweat chloride (Cl- ) concentration is the gold standard for diagnosing cystic fibrosis (CF). This is however, challenging among patients with borderline values. Previous studies have reported that the sweat Cl- /Na+ ratio may be useful for diagnosing CF; however, little is known about Cl- /K+ and (Cl- +Na+ )/K+ ratios. This study aimed to retrospectively define the most appropriate outcome of the sweat test. Samples of sweat were collected using the Gibson and Cooke method. Cl- , Na+ , and K+ were further quantified in 2084 participants-1283 CF and 801 non-CF-based on clinical diagnosis. Among those with borderline sweat Cl- values (n=502), 34.8% had CF. In the receiver operating characteristic curve analysis, the area under the curve was calculated to evaluate the diagnostic value of the ion ratios. In the overall population, all the ratios significantly discriminated CF from non-CF, whereas in the borderline group, only Cl- /Na+ significantly discriminated CF and non-CF subjects, regardless of age. This article is protected by copyright. All rights reserved.

PMID:33822490 | DOI:10.1002/ppul.25395

Cell Microbiol. 2021 Apr 6. doi: 10.1111/cmi.13340. Online ahead of print.

ABSTRACT

Trimeric Autotransporter Adhesins (TAA) found in Gram-negative bacteria play a key role in virulence. This is the case of Burkholderia cepacia complex (Bcc), a group of related bacteria able to cause infections in patients with cystic fibrosis. These bacteria use TAAs, among other virulence factors, to bind to host protein receptors and their carbohydrate ligands. Blocking such contacts is an attractive approach to inhibit Bcc infections. In this study, using an antibody produced against the TAA BCAM2418 from the epidemic strain Burkholderia cenocepacia K56-2, we were able to uncover its roles as an adhesin and the type of host glycan structures that serve as recognition targets. The neutralization of BCAM2418 was found to cause a reduction in the adhesion of the bacteria to bronchial cells and mucins. Moreover, in vivo studies have shown that the anti-BCAM2418 antibody exerted an inhibitory effect during infection in Galleria mellonella. Finally, inferred by glycan arrays, we were able to predict for the first time, host glycan epitopes for a TAA. We show that BCAM2418 favoured binding to 3'sialyl-3-fucosyllactose, histo-blood group A, α-(1,2)-linked Fuc-containing structures, Lewis structures and GM1 gangliosides. Additionally, the glycan microarrays demonstrated similar specificities of Burkholderia species for their most intensely binding carbohydrates. This article is protected by copyright. All rights reserved.

PMID:33822465 | DOI:10.1111/cmi.13340