Spectrochim Acta A Mol Biomol Spectrosc. 2024 Oct 28;327:125332. doi: 10.1016/j.saa.2024.125332. Online ahead of print.

ABSTRACT

This paper reports the trace-level detection of volatile organic compounds (VOCs) like methanol, ethanol, and isopropanol, which are biomarkers for various diseases like diabetes, breast cancer, lung cancer, chronic pulmonary diseases, squamous cancer, cystic fibrosis, chronic liver diseases, chronic kidney diseases and so on. Here, the photoacoustic spectroscopy technique was used for the trace-level detection of these biomarkers using an indigenously designed tunable frequency (1.4 to 4 kHz range) Helmholtz photoacoustic (PA) cell. The study was carried out with UV (266 nm), Mid IR (5.4-7.3 µm) and THz (0.11 THz) range sources to explore and compare the PA signal generated by mentioned samples for different electronic vibrational and rotational level excitations. We achieved a low detection limit (LoD) of the order of 39.3 ppbV, 29.7 ppbV, and 11.6 ppbV for methanol, ethanol, and isopropanol, respectively using this non-invasive cost-effective, and fast technique. In addition, THz-based PA signal for these samples is reported for the first time.

PMID:39500207 | DOI:10.1016/j.saa.2024.125332

Ann Am Thorac Soc. 2024 Nov 5. doi: 10.1513/AnnalsATS.202405-507OC. Online ahead of print.

ABSTRACT

RATIONALE: Epidemiologic studies on asthmatics and in vitro data suggest a protective role of T2 inflammation in SARS-CoV-2 infection.

OBJECTIVE: Using a large, multisite cohort, we studied clinical outcomes following SARS-CoV-2 infection in multiple asthma endotypes and examined the effects of T2-directed biologics in infected asthmatics.in Methods: The National COVID Cohort Collaborative (N3C) Data Enclave was used to identify and stratify asthmatic patients by endotype to include non-T2 and T2 asthmatics, as well as exposure to T2-directed biologic therapy. We evaluated the risk of hospitalization, invasive mechanical ventilation, and 90-day mortality by endotype and exposure to biologics.

RESULTS: For this study, 402,376 patients met inclusion criteria, of which 138,142 (34%) were characterized as non-T2 and 264,234 (66%) as T2 asthmatics, a group further divided into 104,823 (26%) atopic, 84,440 (21%) eosinophilic, and 74,971 (19%) T2-high asthmatic endotypes. Compared to non-T2 asthmatics, atopic and T2-high asthmatics experienced decreased odds of hospitalization, and 90-day mortality. Conversely, eosinophilic asthmatics experienced higher odds of hospitalization, intubation, and 90-day mortality. Exposure to T2-directed biologic therapies did not alter outcomes after propensity score matching. In contrast, maximum eosinophil count and recent systemic corticosteroid use were directly correlated with increased odds of all outcomes.

CONCLUSIONS: COVID-19 outcomes differ depending on asthma endotype, with atopic asthmatics experiencing lower odds and eosinophilic asthmatics experiencing higher odds of deleterious outcomes. T2-directed biologic treatment did not alter these outcomes but recent systemic corticosteroid use predisposes all asthmatics patients to adverse outcomes. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:39499775 | DOI:10.1513/AnnalsATS.202405-507OC

Am J Physiol Lung Cell Mol Physiol. 2024 Nov 5. doi: 10.1152/ajplung.00059.2024. Online ahead of print.

ABSTRACT

Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin® technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Further, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and COPD, pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases, and the feasibility of targeting the Jagged-1/Notch pathway by inhalation.

PMID:39499257 | DOI:10.1152/ajplung.00059.2024

Am J Physiol Lung Cell Mol Physiol. 2024 Nov 5. doi: 10.1152/ajplung.00132.2024. Online ahead of print.

ABSTRACT

Neutrophil elastase (NE), elevated in the cystic fibrosis (CF) airway, causes macrophage phagocytic failure. We previously reported that NE increases the release of protease Calpain-2 in macrophages. We hypothesized that NE mediates macrophage failure through activation of Calpains. We demonstrate that Calpain inhibition rescued NE induced macrophage phagocytic failure in murine alveolar macrophages in both cftr-null and wild type genotypes. We then sought to determine how NE regulates Calpain-2. Human monocyte derived macrophages (hMDM) from persons with CF (PwCF) and non-CF subjects, were treated with NE or control vehicle and cell lysates prepared to evaluate Calpain-2 protein abundance by Western, and Calpain activity by a specific activity kit. Calpain is activated by intracellular calcium and inactivated by an endogenous inhibitor, Calpastatin. Human MDM were thus treated with NE or control vehicle and cell lysates were analyzed for increased intracellular calcium by Fluo-4 assay and for Calpastatin protein abundance by Western. NE increased Calpain-2 protein and activity, degraded Calpastatin, and increased intracellular calcium in macrophages. At baseline there are no differences in Calpain activity, Calpain-2 and Calpastatin expression, and intracellular calcium between CF and non-CF macrophages. NE increased macrophage Calpain-2 protein and Calpain activity by two potential mechanisms: degradation of Calpastatin, and/or increased intracellular calcium. In summary, Calpain inhibition restored NE-induced macrophage phagocytic failure suggesting a potential CFTR-independent target for phagocytic failure in the CF airway.

PMID:39499256 | DOI:10.1152/ajplung.00132.2024

Heliyon. 2024 Oct 11;10(20):e39244. doi: 10.1016/j.heliyon.2024.e39244. eCollection 2024 Oct 30.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is associated with increased resting energy expenditure. However, the introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has resulted in a paradigm shift in nutritional status for many people with CF, with increase body mass index and reduction in the need for nutritional support. While these changes are likely to reflect improved clinical status and an associated downregulation of energy expenditure, they may also reflect drug-induced alterations in metabolic perturbations within CF cells. We hypothesise that some of these changes relate to normalisation of mitochondrial respiration in CF.

METHODS: Using wild-type (WT) and F508del/F508del CFTR human bronchial epithelial cell lines (HBE cell lines) and baby hamster kidney (BHK) cells we examined the impact of ETI on cellular metabolism. We monitored mitochondrial respiration, using Seahorse extracellular flux assays and monitored mitochondrial reactive oxygen species (mROS) and intracellular calcium levels by flow cytometry.

RESULTS: Increased mitochondrial respiration was found in HBE cell lines and BHK cells expressing CFTR F508del/F508del when assessing basal, maximal, spare respiratory capacities and ATP production, as well as increased mitochondrial ROS generated via forward electron transport. ETI significantly decreased basal, maximal, spare respiratory capacity and ATP production to WT levels or below. Calcium blocker, BAPTA-AM normalised mitochondrial respiration, suggesting a calcium-mediated mechanism. ETI decreased intracellular calcium levels in CF cells to the same extent as BAPTA-AM, highlighting the importance of calcium and chloride in mitochondrial respiration in CF.

CONCLUSIONS: CF cell lines exhibit increased mitochondrial respiration, which can be downregulated by ETI therapy through mechanisms involving calcium.

PMID:39498005 | PMC:PMC11532250 | DOI:10.1016/j.heliyon.2024.e39244

Respir Res. 2024 Nov 4;25(1):397. doi: 10.1186/s12931-024-03029-0.

ABSTRACT

BACKGROUND: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.

METHODS: We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.

RESULTS: We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.

CONCLUSIONS: The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.

PMID:39497082 | DOI:10.1186/s12931-024-03029-0

Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2409049121. doi: 10.1073/pnas.2409049121. Epub 2024 Nov 4.

ABSTRACT

Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a model system for understanding the eukaryotic kinases. Using cryoelectron microscopy, we present complex structures of the PKA catalytic subunit (PKA-C) bound to a full-length protein substrate, the cystic fibrosis transmembrane conductance regulator (CFTR)-an ion channel vital to human health. CFTR gating requires phosphorylation of its regulatory (R) domain. Unphosphorylated CFTR engages PKA-C at two locations, establishing two "catalytic stations" near to, but not directly involving, the R domain. This configuration, coupled with the conformational flexibility of the R domain, permits transient interactions of the eleven spatially separated phosphorylation sites. Furthermore, we determined two structures of the open-pore CFTR stabilized by PKA-C, providing a molecular basis to understand how PKA-C stimulates CFTR currents even in the absence of phosphorylation.

PMID:39495916 | DOI:10.1073/pnas.2409049121

Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2407728121. doi: 10.1073/pnas.2407728121. Epub 2024 Nov 4.

ABSTRACT

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both noncatalytically, through binding, and catalytically, through phosphorylation of multiple serines in CFTR's regulatory (R) domain. Here, we identify key molecular determinants of the CFTR/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause noncatalytic and catalytic CFTR stimulation, respectively. Whereas the "substrate site" mediates CFTR phosphorylation, a distinct hydrophobic patch (the "docking site") is responsible for noncatalytic CFTR activation, achieved by stabilizing the R domain in a "released" conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns, we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes noncatalytic, and profoundly slows catalytic, CFTR stimulation. For the F508del CFTR mutant, present in ~90% of CF patients, maximal activation by demyristoylated PKA-C is reduced by ~10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens, we identify virulence factors that demyristoylate PKA-C in vitro, raising the possibility that during recurrent bacterial infections in CF patients, PKA-C demyristoylation may contribute to the exacerbation of lung disease.

PMID:39495914 | DOI:10.1073/pnas.2407728121

Microbiol Spectr. 2024 Nov 4:e0201224. doi: 10.1128/spectrum.02012-24. Online ahead of print.

ABSTRACT

Polymicrobial infections are infections that are caused by multiple pathogens and are common in patients with cystic fibrosis (CF). Although polymicrobial infections are associated with poor treatment responses in CF, the effects of the ecological interactions between co-infecting pathogens on antibiotic sensitivity and treatment outcome are poorly characterized. To this end, we systematically quantified the impact of these effects on the antibiotic sensitivity of Pseudomonas aeruginosa for nine antibiotics in medium conditioned by 13 secondary cystic fibrosis-associated bacterial and fungal pathogens through time-kill assays. We fitted pharmacodynamic models to these kill curves for each antibiotic-species combination and found that interspecies interactions changing the antibiotic sensitivity of P. aeruginosa are abundant. Interactions that lower antibiotic sensitivity are more common than those that increase it, with generally more substantial reductions than increases in sensitivity. For a selection of co-infecting species, we performed pharmacokinetic-pharmacodynamic modeling of P. aeruginosa treatment. We predicted that interspecies interactions can either improve or reduce treatment response to the extent that treatment is rendered ineffective from a previously effective antibiotic dosing schedule and vice versa. In summary, we show that quantifying the ecological interaction effects as pharmacodynamic parameters is necessary to determine the abundance and the extent to which these interactions affect antibiotic sensitivity in polymicrobial infections.IMPORTANCEIn cystic fibrosis (CF) patients, chronic respiratory tract infections are often polymicrobial, involving multiple pathogens simultaneously. Polymicrobial infections are difficult to treat as they often respond unexpectedly to antibiotic treatment, which might possibly be explained because co-infecting pathogens can influence each other's antibiotic sensitivity, but it is unknown to what extent such effects occur. To investigate this, we systematically quantified the impact of co-infecting species on antibiotic sensitivity, focusing on P. aeruginosa, a common CF pathogen. We studied for a large set co-infecting species and antibiotics whether changes in antibiotic response occur. Based on these experiments, we used mathematical modeling to simulate P. aeruginosa's response to colistin and tobramycin treatment in the presence of multiple pathogens. This study offers comprehensive data on altered antibiotic sensitivity of P. aeruginosa in polymicrobial infections, serves as a foundation for optimizing treatment of such infections, and consolidates the importance of considering co-infecting pathogens.

PMID:39495005 | DOI:10.1128/spectrum.02012-24

Front Microbiol. 2024 Oct 18;15:1476041. doi: 10.3389/fmicb.2024.1476041. eCollection 2024.

ABSTRACT

Burkholderia cepacia complex is a cause of serious lung infections in people with cystic fibrosis, exhibiting extremely high levels of antimicrobial resistance. These infections are difficult to treat and are associated with high morbidity and mortality. With a notable lack of new antibiotic classes currently in development, exploring alternative antimicrobial strategies for Burkholderia cepacia complex is crucial. One potential alternative seeing renewed interest is the use of bacteriophage (phage) therapy. This review summarises what is currently known about Burkholderia cepacia complex in cystic fibrosis, as well as challenges and insights for using phages to treat Burkholderia cepacia complex lung infections.

PMID:39493847 | PMC:PMC11527634 | DOI:10.3389/fmicb.2024.1476041

Magn Reson Imaging. 2024 Nov 2:110271. doi: 10.1016/j.mri.2024.110271. Online ahead of print.

ABSTRACT

Hyperpolarized Xenon MRI (HPG MRI) has been studied for its potential use in assessing lung function in patients with cystic fibrosis (CF) and in patients with asthma. We present a case of a man with overlapping cystic fibrosis and allergic asthma with severe obstructive lung disease in which spirometry and computed topography (CT) imaging was unable to determine the primary cause for his uncontrolled symptoms. HPG MRI was used to guide a tissue biopsy and determine the primary driver to be allergic asthma. After starting targeted therapy for severe asthma, his symptoms have greatly improved.

PMID:39491568 | DOI:10.1016/j.mri.2024.110271

Pulm Pharmacol Ther. 2023 Oct 27:102264. doi: 10.1016/j.pupt.2023.102264. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term changes in medication dispensings post cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation have not been described. Our study aimed to investigate changes in medication use following the initiation of modulator therapy in people with cystic fibrosis (PwCF) in Australia.

METHODS: Using a 10% sample of the Australian Pharmaceutical Benefits Scheme (PBS) data between 2013 and 2022, linear regression was used to analyse dispensings in PwCF who initiated any modulator (cases) and matched PwCF controls not dispensed a modulator. The difference in mean number of total monthly dispensings pre- and post-modulator initiation was analysed, with separate analyses by medication class.

RESULTS: A total of 247 cases were matched 1:1 to controls (case and control median age 21 years (IQR: 13-32), 55.1% male). Immediately after modulator initiation, the mean number of dispensings was 0.9 higher in the modulator group, but then decreased to the level of controls after approximately 5 years. After 7.5 years, cases had decreased opioids compared to the pre-modulator period (β-coefficient: -0.00131, 95% CI: -0.00164, -0.00097) whilst controls did not (β: -0.00014, 95% CI: -0.00042, 0.00014). Over the same time period controls had an increase in psychotropics (β: 0.00389, 95% CI:0.00295, 0.00484) whilst cases remained stable (β: -0.00014, 95% CI: -0.0006, 0.00031). Women's health medications increased in cases (β:0.00026, 95% CI:0.0001, 0.00042) but decreased in controls (β: 0.00044, 95% CI: 0.00063, -0.00025).

CONCLUSIONS: Modulator initiation in PwCF was associated with decreased dispensings of opioids and psychotropics, and increased dispensings of women's health medications, suggesting improved patient outcomes across multiple clinical domains.

PMID:39491231 | DOI:10.1016/j.pupt.2023.102264

Chest. 2024 Oct 25:S0012-3692(24)05418-7. doi: 10.1016/j.chest.2024.10.029. Online ahead of print.

ABSTRACT

BACKGROUND: Serum anti-glycopeptidolipid (GPL) core immunoglobuin A (IgA) antibody test has been proposed as a diagnostic tool for Mycobacterium avium complex pulmonary diseases. Cross-reactivity with other non-tuberculous mycobacteria (NTM), including M. abscessus, indicates that it may have a role as a broader screening test for NTM pulmonary disease (NTM-PD). NTM-PD is believed to be underdiagnosed in patients with bronchiectasis.

RESEARCH QUESTION: Can the serum anti-GPL core IgA antibody test be used to screen for NTM-PD in bronchiectasis?

STUDY DESIGN AND METHODS: Patients from the prospective European Bronchiectasis Registry (EMBARC-BRIDGE; NCT03791086) were enrolled. Patients from the United Kingdom, Italy, Spain, Belgium, the Netherlands, and Germany were included. A control cohort of patients without any underlying lung disease was also recruited. The levels of serum IgA antibodies against the GPL core were measured using an enzyme immunoassay kit, and receiver operating characteristics curve analysis was conducted to evaluate the accuracy of the antibody level in screening for NTM-PD.

RESULTS: 282 patients were enrolled (151 [53.6%] female, median age 68 years). Median (quartile 1-3) anti-GPL-core IgA antibody levels were 0.2 (0.1-0.3) U/mL in patients without NTM isolation and NTM-PD (n=238), 0.3 (0.2-0.4) U/mL in NTM isolation that were incompatible with the diagnosis of NTM-PD (n=18) and 1.5 (0.4-6.2) U/mL in NTM-PD (n=26) (P=0.0001). Antibody levels showed excellent accuracy in identifying patients with NTM-PD (area under the curve 0.886, 95% CI 0.800-0.973) in bronchiectasis cohort and also showed excellent discrimination of patients with NTM-PD from those with NTM isolation who did not meet the diagnostic criteria for NTM-PD (0.816, 95% CI 0.687-0.945).

INTERPRETATION: The anti-GPL-core IgA antibody demonstrated excellent efficacy in screening for NTM-PD in a large bronchiectasis cohort.

PMID:39490969 | DOI:10.1016/j.chest.2024.10.029

Respir Med. 2024 Oct 25:107847. doi: 10.1016/j.rmed.2024.107847. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) outpatient care has evolved into a hybrid model, incorporating telehealth and face-to-face reviews. This study explores the acceptability of the hybrid model of care from the perspective of people with CF and parents of children with CF.

METHODS: People with CF and parents of children with CF from eight Australian CF centres participated in semi-structured interviews. Maximum variation sampling sought participants from varied socioeconomic levels and geographical locations. The interview guide and thematic analysis utilised the Theoretical Framework of Acceptability (TFA) to explore domains of acceptability.

RESULTS: Ten adults and 16 parents of children with CF were interviewed. The major themes from the interviews aligned with the TFA domains. These were: (1) life is easier with a hybrid model of care, (2) hybrid care is effective but not comprehensive, (3) hybrid care needs to adapt to individual needs, (4) confidence in hybrid care is determined by internal and external factors, (5) hybrid care is easy to engage in (6) accepting hybrid care involves compromising valued aspects of face-to-face care, (7) hybrid care reduces infection risk and helps normalise life.

CONCLUSION: The addition of telehealth to the traditional model of CF care is acceptable overall. The level of acceptability is variable and is determined by the willingness to compromise valued aspects of face-to-face care to obtain the convenience, safety and normality that receiving part of care through telehealth allows. Therefore, the model should be personalised in consultation with people with CF and parents of children with CF.

PMID:39490937 | DOI:10.1016/j.rmed.2024.107847

Int J Pharm. 2024 Oct 26:124871. doi: 10.1016/j.ijpharm.2024.124871. Online ahead of print.

ABSTRACT

Azole-resistant Aspergillus fumigatus (A. fumigatus) is an emerging worldwide pathogen. Pulmonary aspergillosis primarily affects severely immunocompromised patients and is also a particularly critical condition for cystic fibrosis (CF) patients. A recently designed gallium polypyridyl catecholate complex, GaS1, has previously demonstrated in vitro and in vivo antimicrobial activity against Gram-negative bacteria. In the present work GaS1 activity was assessed against A. fumigatus clinical isolates in a novel air-liquid-interface lung infection model, mimicking the conditions found in the CF airways. Furthermore, in this study both a solution for nebulisation and dry powders for inhalation were developed with a view to optimising GaS1 delivery to the lung. The solution for nebulisation was characterised for its osmolality and pH, while the dry powders were characterised by scanning electron microscopy, powder X-ray diffraction, thermal analysis and laser light scattering particle size analysis. The aerodynamic deposition profiles of all formulations were determined using a next generation impactor. GaS1, tested in a concentration range of 0.016-0.5 mg/mL, inhibited the growth of A. fumigatus lung isolates in a complex host-environment-mimicking medium at the non-toxic concentration of 0.063 mg/mL. A marked dose-dependent antifungal activity of GaS1 was also observed in the presence of differentiated human distal lung epithelial cells (NCI-H441) at the air liquid interface, with nearly no fungal growth detected at the macroscopic and microscopic level. A solution for nebulisation and three different dry powder inhaler formulations, prepared by spray-drying GaS1 with different concentrations of L-leucine, displayed suitable aerodynamic characteristics for GaS1 delivery to the lungs, while maintaining excellent antifungal activity. Overall, the results obtained highlight the potential of gallium-polypyridyl catecholate complexes for the management of difficult-to-treat A. fumigatus pulmonary infections.

PMID:39490551 | DOI:10.1016/j.ijpharm.2024.124871

Gen Hosp Psychiatry. 2024 Oct 16:S0163-8343(24)00214-7. doi: 10.1016/j.genhosppsych.2024.10.009. Online ahead of print.

NO ABSTRACT

PMID:39490334 | DOI:10.1016/j.genhosppsych.2024.10.009

J Cyst Fibros. 2024 Oct 25:S1569-1993(24)01786-7. doi: 10.1016/j.jcf.2024.09.018. Online ahead of print.

ABSTRACT

BACKGROUND: The Pseudomonas filamentous bacteriophage (Pf) infects Pseudomonas aeruginosa (Pa) and is abundant in the airways of many people with cystic fibrosis (CF) (pwCF). We previously demonstrated that Pf promotes biofilm growth, as well as generates liquid crystals that confer biofilms with adhesivity, viscosity and resistance to clearance. Consistent with these findings, the presence of Pf in sputum from pwCF has been linked to chronic Pa infection and more severe exacerbations in a cross-sectional cohort study.

METHODS: We examined the relationships between Pf and clinical outcomes in a longitudinal study of pwCF. Sputum Pa and Pf concentrations were measured by qPCR, as well cytokines and active neutrophil elastase by standardized assays. Recorded clinical data, including spirometry and microbiological results, were analyzed for associations with Pf. Finally, lung explants from pwCF in this cohort who underwent lung transplantation were examined for presence of liquid crystals within secretions.

RESULTS: In explanted lungs from pwCF with known Pf infection we demonstrate areas of birefringence consistent with liquid crystalline structures within the airways. We find that high concentration of Pf in sputum is associated with accelerated loss of lung function, suggesting a potential role for Pf in the pathogenesis of CF lung disease. We also find Pf to associate with increased airway inflammation and an anti-viral cytokine response.

CONCLUSION: Pf may serve as a prognostic biomarker and potential therapeutic target for Pa infections in CF.

PMID:39490215 | DOI:10.1016/j.jcf.2024.09.018

J Cyst Fibros. 2024 Oct 25:S1569-1993(24)01795-8. doi: 10.1016/j.jcf.2024.10.002. Online ahead of print.

NO ABSTRACT

PMID:39490214 | DOI:10.1016/j.jcf.2024.10.002

Int J Med Microbiol. 2024 Oct 22;317:151639. doi: 10.1016/j.ijmm.2024.151639. Online ahead of print.

ABSTRACT

We aimed to access the genetic diversity of Apergillus fumigatus strains obtained from cystic fibrosis (CF) patients from southern Brazil. A. fumigatus sensu stricto isolates from respiratory clinical specimens were genotyped by microsatellite markers and azole resistance was evaluated by azole-agar screening. Twenty-seven isolates from twenty-seven patients showed a high genetic diversity, with the differentiation of 25 different genotypes (25 unique and one common to two isolates). All isolates were susceptible to the azoles tested. We believe that prospectively monitoring A. fumigatus genetic diversity is essential to identify interpatient transmission and outbreaks, as is the identification of resistant strains.

PMID:39490213 | DOI:10.1016/j.ijmm.2024.151639

Nat Commun. 2024 Nov 3;15(1):9500. doi: 10.1038/s41467-024-53923-w.

ABSTRACT

Supercoiled flagellar filaments function as mechanical propellers within the bacterial flagellum complex, playing a crucial role in motility. Flagellin, the building block of the filament, features a conserved inner D0/D1 core domain across different bacterial species. In contrast, approximately half of the flagellins possess additional, highly divergent outer domain(s), suggesting varied functional potential. In this study, we report atomic structures of flagellar filaments from three distinct bacterial species: Cupriavidus gilardii, Stenotrophomonas maltophilia, and Geovibrio thiophilus. Our findings reveal that the flagella from the facultative anaerobic G. thiophilus possesses a significantly more negatively charged surface, potentially enabling adhesion to positively charged minerals. Furthermore, we analyze all AlphaFold predicted structures for annotated bacterial flagellins, categorizing the flagellin outer domains into 682 structural clusters. This classification provides insights into the prevalence and experimental verification of these outer domains. Remarkably, two of the flagellar structures reported herein belong to a distinct cluster, indicating additional opportunities on the study of the functional diversity of flagellar outer domains. Our findings underscore the complexity of bacterial flagellins and open up possibilities for future studies into their varied roles beyond motility.

PMID:39489766 | DOI:10.1038/s41467-024-53923-w