Allergy. 2021 Mar;76(3):961-962. doi: 10.1111/all.14593.

NO ABSTRACT

PMID:33675253 | DOI:10.1111/all.14593

Appl Environ Microbiol. 2021 Mar 5:AEM.00061-21. doi: 10.1128/AEM.00061-21. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen causing life-threatening infections. Previously, we showed that elevated calcium (Ca2+) levels increase the production of virulence factors in P. aeruginosa In the effort to characterize the Ca2+ regulatory network, we identified a Ca 2+- r egulated β- p ropeller protein, CarP, and showed that expression of the encoding gene is controlled by the Ca2+-regulated two-component system CarSR. Here, by using a Galleria melonella model, we showed that CarP plays a role in regulating P. aeruginosa virulence. By using RNA-Seq, RT-PCR, RT-qPCR, and promoter fusions, we determined that carP is transcribed into at least two transcripts and regulated by several bacterial and host factors. The transcription of carP is elevated in response to Ca2+ in P. aeruginosa cystic fibrosis isolates and PAO1 laboratory strain. Elevated Fe2+ also induces carP Simultaneous addition of Ca2+ and Fe2+ increased the carP promoter activity synergistically, which requires the presence of CarR. In silico analysis of the intergenic sequence upstream of carP predicted recognition sites of RhlR/LasR, OxyR, and LexA, suggesting regulation by quorum sensing (QS) and oxidative stress. In agreement, the carP promoter was activated in response to stationary-phase PAO1 supernatant and required the presence of elevated Ca2+ and CarR, but remained silent in the triple mutant lacking rhlI, lasI, and pqsA synthases. We also showed that carP transcription is regulated by oxidative stress and that CarP contributes to P. aeruginosa Ca2+-dependent H2O2 tolerance. The multifactorial regulation of carP suggests that CarP plays an important role in P. aeruginosa adaptations to host environments.IMPORTANCE P. aeruginosa is a human pathogen causing life-threatening infections. It is particularly notorious for its ability to adapt to diverse environments within the host. Understanding the signals and the signaling pathways enabling P. aeruginosa adaptation is imperative for developing effective therapies to treat infections caused by this organism. One host signal of particular importance is calcium. Previously, we identified a component of P. aeruginosa calcium-signaling network, CarP, whose expression is induced by elevated levels of calcium. Here we show that carP plays an important role in P. aeruginosa virulence and is up-regulated in P. aeruginosa strains isolated from sputa of patients with cystic fibrosis. We also identified several bacterial and host factors that regulate the transcription of carP Such multifactorial regulation highlights the interconnectedness between regulatory circuits and together with the pleotropic effect of CarP on virulence suggests the importance of this protein in P. aeruginosa adaptations to the host.

PMID:33674436 | DOI:10.1128/AEM.00061-21

J Cyst Fibros. 2021 Mar 2:S1569-1993(21)00042-4. doi: 10.1016/j.jcf.2021.02.007. Online ahead of print.

ABSTRACT

BACKGROUND: The CFTR modulator ivacaftor has been variably effective in treating individuals with cystic fibrosis (CF) who harbor CFTR gating variants such as G551D, as well as other classes of CFTR variants when used with other modulators. Because CFTR genotype does not fully explain this variability, defining genetic modifiers of response to modulator therapy is of particular interest to the field of individualized CF drug therapy. Previous studies have proposed that a variant in SLC26A9 (rs7512462) is associated with lung disease severity and with response to treatment with ivacaftor in individuals with CF who carry G551D or gating variants.

METHODS: Given the implications for CF treatment, we re-examined the reported associations in three cohorts; patients enrolled in the Twin and Siblings study at Johns Hopkins University, the CF modifier study at the University of North Carolina at Chapel Hill, and the prospective G551D Observational (GOAL) study. The GOAL study was specifically designed to measure lung function response to ivacaftor.

RESULTS: We find no association between SLC26A9 (rs7512462) genotype and lung disease severity (n = 272) or change in lung function at one-, three-, and six-month intervals following ivacaftor treatment(n = 141) in individuals with CF who carry at least one G551D variant.

CONCLUSIONS: Our inability to replicate this association indicates that rs7512462 genotype should not be used in treatment decisions.

PMID:33674211 | DOI:10.1016/j.jcf.2021.02.007

J Cyst Fibros. 2021 Mar 2:S1569-1993(21)00040-0. doi: 10.1016/j.jcf.2021.02.005. Online ahead of print.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD) affects 40-50% of adult patients with cystic fibrosis. Insulin therapy is recommended but there are therapeutic challenges, particularly risk of hypoglycemia and aversion of some patients to injectables. An oral incretin-based therapy using a DPP-4i (dipeptidyl peptidase-4 inhibitor), may be a reasonable option, especially in the early stage of the disease. The effect of chronic incretin-based therapy on CFRD is unknown. Here is a report of 3 cases of CFRD patients treated with sitagliptin and the response to therapy over a period of 5-10 years. An effective glycemic control was demonstrated in all the patients, at least during the first 5 years of sitagliptin treatment, and the benefit persisted for a decade in two of them. The secondary failure of the DPP-4i occurred in a CFRD patient with a phenotype resembling type 2 diabetes. A DPP-4i may have an important role in the management of CFRD.

PMID:33674210 | DOI:10.1016/j.jcf.2021.02.005

Rev Argent Microbiol. 2021 Mar 2:S0325-7541(21)00008-0. doi: 10.1016/j.ram.2020.12.005. Online ahead of print.

ABSTRACT

Bacteria of the Streptococcus anginosus group (SAG) have recently been recognized as contributors of bronchopulmonary disease in cystic fibrosis (CF). Routine detection and quantification are limited by current CF microbiology protocols. The development of the CHROMagar™ StrepB chromogenic medium modified by the addition of plasma, nalidixic acid, colistin and sulfadiazine to make it selective for SAG bacteria is described. This medium could be used as a diagnostic tool to detect SAG in respiratory samples from patients suffering from chronic lung disease.

PMID:33674170 | DOI:10.1016/j.ram.2020.12.005

Viruses. 2021 Feb 20;13(2):330. doi: 10.3390/v13020330.

ABSTRACT

Human bocavirus 1 (HBoV1) has gained attention as a gene delivery vector with its ability to infect polarized human airway epithelia and 5.5 kb genome packaging capacity. Gorilla bocavirus 1 (GBoV1) VP3 shares 86% amino acid sequence identity with HBoV1 but has better transduction efficiency in several human cell types. Here, we report the capsid structure of GBoV1 determined to 2.76 Å resolution using cryo-electron microscopy (cryo-EM) and its interaction with mouse monoclonal antibodies (mAbs) and human sera. GBoV1 shares capsid surface morphologies with other parvoviruses, with a channel at the 5-fold symmetry axis, protrusions surrounding the 3-fold axis and a depression at the 2-fold axis. A 2/5-fold wall separates the 2-fold and 5-fold axes. Compared to HBoV1, differences are localized to the 3-fold protrusions. Consistently, native dot immunoblots and cryo-EM showed cross-reactivity and binding, respectively, by a 5-fold targeted HBoV1 mAb, 15C6. Surprisingly, recognition was observed for one out of three 3-fold targeted mAbs, 12C1, indicating some structural similarity at this region. In addition, GBoV1, tested against 40 human sera, showed the similar rates of seropositivity as HBoV1. Immunogenic reactivity against parvoviral vectors is a significant barrier to efficient gene delivery. This study is a step towards optimizing bocaparvovirus vectors with antibody escape properties.

PMID:33672786 | DOI:10.3390/v13020330

J Fungi (Basel). 2021 Feb 20;7(2):152. doi: 10.3390/jof7020152.

ABSTRACT

Molecular fungal genotyping techniques developed and employed for epidemiological studies have understandably concentrated on establishing the genetic diversity of Aspergillus fumigatus in invasive aspergillosis due to its severity, the urgency for treatment, and the need to demonstrate possible sources. Some early studies suggested that these strains were phenotypically, if not genotypically, different from others. However, with improved discrimination and evaluations, incorporating environmental as well as clinical isolates from other Aspergillus conditions (e.g., chronic pulmonary aspergillosis and cystic fibrosis), this premise is no longer upheld. Moreover, with the onset of increased global triazole resistance, there has been a concerted effort to incorporate resistance profiling into genotyping studies and the realisation that the wider population of non-immunocompromised aspergillosis patients are at risk. This review summarises the developments in molecular genotyping studies that incorporate resistance profiling with attention to chronic pulmonary aspergillosis and an example of our UK experience.

PMID:33672698 | DOI:10.3390/jof7020152

Biomedicines. 2021 Feb 20;9(2):216. doi: 10.3390/biomedicines9020216.

ABSTRACT

A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

PMID:33672477 | DOI:10.3390/biomedicines9020216

Int J Mol Sci. 2021 Feb 22;22(4):2175. doi: 10.3390/ijms22042175.

ABSTRACT

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca2+-activated K+ channel (BKCa) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca2+ imaging, and computational modeling, we evaluated the effects of S1P on the Ca2+-activated K+ currents (IK(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BKCa channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca2+ concentration (Cai) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BKCa was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed IK(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of IK(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced IK(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BKCa conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited IK(Ca) and the permissive role of S1P on the BKCa activity was also effectively observed in the PC12 cell system. The S1P-mediated IK(Ca) stimulation may result from the elevated Cai, whereas the inhibition of BKCa activity by S1P appears to be direct. By the differentiated tailoring BKCa channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells.

PMID:33671654 | DOI:10.3390/ijms22042175

Metabolites. 2021 Feb 22;11(2):123. doi: 10.3390/metabo11020123.

ABSTRACT

Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF-both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis.

PMID:33671639 | DOI:10.3390/metabo11020123

Int J Mol Sci. 2021 Feb 22;22(4):2155. doi: 10.3390/ijms22042155.

ABSTRACT

The treatment of lung infection in the context of cystic fibrosis (CF) is limited by a biofilm mode of growth of pathogenic organisms. When compared to planktonically grown bacteria, bacterial biofilms can survive extremely high levels of antimicrobials. Within the lung, bacterial biofilms are aggregates of microorganisms suspended in a matrix of self-secreted proteins within the sputum. These structures offer both physical protection from antibiotics as well as a heterogeneous population of metabolically and phenotypically distinct bacteria. The bacteria themselves and the components of the extracellular matrix, in addition to the signaling pathways that direct their behaviour, are all potential targets for therapeutic intervention discussed in this review. This review touches on the successes and failures of current anti-biofilm strategies, before looking at emerging therapies and the mechanisms by which it is hoped they will overcome current limitations.

PMID:33671516 | DOI:10.3390/ijms22042155

Nutrients. 2021 Feb 17;13(2):655. doi: 10.3390/nu13020655.

ABSTRACT

Both genetic and environmental factors are involved in the onset of inflammatory bowel disease (IBD). In particular, diet composition is suspected to significantly contribute to IBD risk. In recent years, major interest has raised about the role of nutrition in disease pathogenesis and course, and many studies have shown a clear link between diet composition and intestinal permeability impairment. Moreover, many IBD-related factors, such as poor dietary intake, nutrients loss and drugs interact with nutritional status, thus paving the way for the development of many therapeutic strategies in which nutrition represents the cornerstone, either as first-line therapy or as reversing nutritional deficiencies and malnutrition in IBD patients. Exclusive enteral nutrition (EEN) is the most rigorously supported dietary intervention for the treatment of Crohn's Disease (CD), but is burdened by a low tolerability, especially in pediatric patients. Promising alternative regimens are represented by Crohn's Disease Exclusion Diet (CDED), and other elimination diets, whose use is gradually spreading. The aim of the current paper is to provide a comprehensive and updated overview on the latest evidence about the role of nutrition and diet in pediatric IBD, focusing on the different nutritional interventions available for the management of the disease.

PMID:33671453 | DOI:10.3390/nu13020655

Microorganisms. 2021 Feb 19;9(2):435. doi: 10.3390/microorganisms9020435.

ABSTRACT

The immunocompromised airways are susceptible to infections caused by a range of pathogens which increases the opportunity for polymicrobial interactions to occur. Pseudomonas aeruginosa and Staphylococcus aureus are the predominant causes of pulmonary infection for individuals with respiratory disorders such as cystic fibrosis (CF). The spore-forming fungus Aspergillus fumigatus, is most frequently isolated with P. aeruginosa, and co-infection results in poor outcomes for patients. It is therefore clinically important to understand how these pathogens interact with each other and how such interactions may contribute to disease progression so that appropriate therapeutic strategies may be developed. Despite its persistence in the airways throughout the life of a patient, A. fumigatus rarely becomes the dominant pathogen. In vitro interaction studies have revealed remarkable insights into the molecular mechanisms that drive agonistic and antagonistic interactions that occur between A. fumigatus and pulmonary bacterial pathogens such as P. aeruginosa. Crucially, these studies demonstrate that although bacteria may predominate in a competitive environment, A. fumigatus has the capacity to persist and contribute to disease.

PMID:33669831 | DOI:10.3390/microorganisms9020435

Nutrients. 2021 Feb 19;13(2):669. doi: 10.3390/nu13020669.

ABSTRACT

BACKGROUND: The use of oral nutritional supplements (ONS) is common practice in patients suffering from cystic fibrosis (CF). We aimed to describe the rate of ONS use to assess their contribution to dietary intake and to determine if they are associated with respiratory status, body composition, muscle strength, bone mineral density (BMD), bone remodeling biomarkers, and plasmatic levels of vitamins.

METHODS: Cross-sectional study. Patients were clinically stable adults recruited from the CF unit. A 4-day prospective dietary questionnaire was conducted; in addition to respiratory variables, body composition, and BMD (through densitometry, DXA), muscle strength (JAMAR dynamometer), fat-soluble vitamins, and bone remodeling biomarkers (vitamins A, D, and E; osteocalcin, OC; undercarboxylated osteocalcin, ucOC; degradation of the C-terminal telopeptides of type I collagen, CTX; and receptor activator of nuclear factor-kappaB ligand, RANKL) were also evaluated.

RESULTS: The study included 59 subjects with CF (57.6% female, mean age 29.3 ± 9.4 years, and BMI 22.0 ± 3.6 kg/m2). In this study, 22% (13) patients were taking ONS and presented, compared with those not taking them, significantly more total and mild exacerbations and lower BMI; moreover, they showed a significantly higher total daily calorie intake in addition to a higher consumption of carbohydrates, proteins, and lipids per kg of body weight, omega-3 fatty acids, and vitamins A, D, and E. Vitamin E plasmatic levels were significantly higher in the group on ONS, as was the case with RANKL; finally, a lower rate of vitamin D deficiency was also found.

CONCLUSIONS: ONS were used by patients with worse respiratory and nutritional statuses and their use was associated with a higher intake of macro- and micronutrients and with better plasmatic levels of fat-soluble vitamins.

PMID:33669612 | DOI:10.3390/nu13020669

Biomolecules. 2021 Feb 19;11(2):313. doi: 10.3390/biom11020313.

ABSTRACT

BACKGROUND: Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation.

METHODS: The study involved 55 CF patients and 45 healthy subjects (HS). Sterol concentrations (μg/dL) were measured by gas chromatography/mass spectrometry. CF was characterised by lung function, pancreatic status, liver disease and diabetes coexistence, Pseudomonas aeruginosa colonisation and BMI. CFTR genotypes were classified as severe or other.

RESULTS: Campesterol and β-sitosterol concentrations were lower (p = 0.0028 and p < 0.0001, respectively) and lathosterol levels (reflecting endogenous cholesterol biosynthesis) were higher (p = 0.0016) in CF patients than in HS. Campesterol and β-sitosterol concentrations were lower in patients with a severe CFTR genotype, pancreatic insufficiency and lower pancreatic enzyme dose (lipase units/gram of fat). In multiple regression analyses, β-sitosterol and campesterol concentrations were predicted by genotype and pancreatic insufficiency, whereas cholesterol and its fractions were predicted by phytosterol concentrations, age, dose of pancreatic enzymes, nutritional status and genotype.

CONCLUSIONS: Independent determinants of lipid status suggest that malabsorption and pancreatic enzyme supplementation play a significant role in sterol abnormalities. The measurement of campesterol and β-sitosterol concentrations in CF patients may serve for the assessment of the effectiveness of pancreatic enzyme replacement therapy and/or compliance, but further research is required.

PMID:33669566 | DOI:10.3390/biom11020313

Diagnostics (Basel). 2021 Feb 16;11(2):321. doi: 10.3390/diagnostics11020321.

ABSTRACT

Cystic Fibrosis (CF) registries are an essential resource of epidemiological and clinical data. Although the median age at diagnosis is usually reported in the first months of life, a minority of individuals is diagnosed during adulthood. The aim of this study was to describe demographic, genetic, and clinical characteristics of this subgroup of the Italian CF population by using data from the Italian CF Registry (ICFR). Patients ≥18 years at diagnosis were selected and clinical data at diagnosis were analyzed from the 2012-2018 ICFR data (Cohort A). Subjects with diagnosis ≥18 years were selected from 2018 ICFR dataset (Cohort B) to describe their clinical status. In 2012-18 the incidence of late diagnosis was 18.2%, whereas, in 2018, the prevalence of patients diagnosed ≥18 years was 12.54%. The median age of late diagnosis was 36.2 years, ranging from 19.0 to 68.3. The male patients were diagnosed because of infertility in the 45.9% of cases. Median sweat chloride value (SCL) was 69 mmol/L (range 9-150). F508del mutation accounted for 28.3% of alleles. A wide variability in respiratory function was present with a median percent predicted Forced Expiratory Volume in the first second (ppFEV1) of 90.8% (range 20-147%). Low prevalence of pancreatic insufficiency (25%) and of Pseudomonas aeruginosa (Pa) infection (17%) suggest a mild CF phenotype in the majority of patients. The assessment of the clinical status in the 2018 dataset and the comparison between genders showed a greater nutritional and respiratory impairment in females. Further studies are needed to clarify the importance of a true diagnostic delay or of late onset of CF symptoms.

PMID:33669477 | DOI:10.3390/diagnostics11020321

J Pers Med. 2021 Feb 16;11(2):132. doi: 10.3390/jpm11020132.

ABSTRACT

Individuals with cystic fibrosis (CF) often experience gastrointestinal (GI) abnormalities. In recent years, the intestinal microbiome has been postulated as a contributor to the development of CF-associated GI complications, hence representing a potential therapeutic target for treatment. We recently developed a rabbit model of CF, which is shown to manifest many human patient-like pathological changes, including intestinal obstruction. Here, we investigated the feces microbiome in young CF rabbits in the absence of antibiotics treatment. Stool samples were collected from seven- to nine-week-old CF rabbits (n = 7) and age-matched wild-type (WT) rabbits (n = 6). Microbiomes were investigated by iTag sequencing of 16S rRNA genes, and functional profiles were predicted using PICRUSt. Consistent with reports of those in pediatric CF patients, the fecal microbiomes of CF rabbits are of lower richness and diversity than that of WT rabbits, with a marked taxonomic and inferred functional dysbiosis. Our work identified a new CF animal model with the manifestation of intestinal dysbiosis phenotype. This model system may facilitate the research and development of novel treatments for CF-associated gastrointestinal diseases.

PMID:33669429 | DOI:10.3390/jpm11020132

Int J Mol Sci. 2021 Feb 16;22(4):1952. doi: 10.3390/ijms22041952.

ABSTRACT

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

PMID:33669352 | DOI:10.3390/ijms22041952

Biomolecules. 2021 Feb 25;11(3):351. doi: 10.3390/biom11030351.

ABSTRACT

The ability to regulate the recruitment of immune cells makes chemokines and their receptors attractive drug targets in many inflammatory diseases. Based on its preferential expression on T helper type 2 (Th2) cells, C-C chemokine receptor type 4 (CCR4) has been widely studied in the context of allergic diseases, but recent evidence on the expression of CCR4 in other cell types has considerably expanded the potential applications of CCR4 antagonism. However, the current number of approved indications, as well as the portfolio of CCR4-targeting drugs, are still limited. In the present study, we have assessed the potential therapeutic efficacy of a CCR4 small molecule antagonist, SP50, discovered via an in silico-based approach, against a variety of pre-clinical settings of infection with the fungus Aspergillus fumigatus. We show that SP50 efficiently worked as prophylactic vaccine adjuvant in immunocompetent mice, protected against invasive aspergillosis in immunosuppressed mice. Further, the CCR4 antagonist prevented allergic bronchopulmonary aspergillosis in susceptible mice, and in a murine model of cystic fibrosis, a genetic disorder characterized by chronic pulmonary inflammation and recurrent infections. In conclusion, our results extend the potential applications of CCR4 antagonism and prompt for the development of novel compounds with the potential to progress to clinical trials.

PMID:33669094 | DOI:10.3390/biom11030351

Cells. 2021 Feb 25;10(3):495. doi: 10.3390/cells10030495.

ABSTRACT

Increasing antimicrobial resistance due to misuse and overuse of antimicrobials, as well as a lack of new and innovative antibiotics in development has become an alarming global threat. Preventative therapeutics, like vaccines, are combative measures that aim to stop infections at the source, thereby decreasing the overall use of antibiotics. Infections due to Gram-negative pathogens pose a significant treatment challenge because of substantial multidrug resistance that is acquired and spread throughout the bacterial population. Burkholderia spp. are Gram-negative intrinsically resistant bacteria that are responsible for environmental and nosocomial infections. The Burkholderia cepacia complex are respiratory pathogens that primarily infect immunocompromised and cystic fibrosis patients, and are acquired through contaminated products and equipment, or via patient-to-patient transmission. The Burkholderia pseudomallei complex causes percutaneous wound, cardiovascular, and respiratory infections. Transmission occurs through direct exposure to contaminated water, water-vapors, or soil, leading to the human disease melioidosis, or the equine disease glanders. Currently there is no licensed vaccine against any Burkholderia pathogen. This review will discuss Burkholderia vaccine candidates derived from outer membrane proteins, OmpA, OmpW, Omp85, and Bucl8, encompassing their structures, conservation, and vaccine formulation.

PMID:33668922 | DOI:10.3390/cells10030495