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Lung Infections (lung + infections)
Selected AbstractsNovel conjugate vaccine for the prevention of Pseudomonas aeruginosa infection in cystic fibrosis patientsDRUG DEVELOPMENT RESEARCH, Issue 8 2007Kelly L. Matson Abstract The published literature evaluating the safety and immunogenicity of the polyvalent O-polysaccharide-toxin A conjugate vaccine is reviewed. Primary immunization followed by annual booster significantly reduced the incidence of chronic Pseudomonas aeruginosa lung infections (particularly mucoid phenotype strains) and extended time to infection. The findings reflected lower frequency of P. aeruginosa in sputum/throat cultures and preservation of lung function. Additionally, studies indicated higher binding affinity of vaccine-induced anti-lipopolysaccharide (LPS) compared with infection-induced anti-LPS serum immunoglobulin G antibodies, suggesting protective capacity. P. aeruginosa prophylaxis with the conjugate vaccine in cystic fibrosis patients has proved safe and useful in preventing and delaying chronic lung infection. Drug Dev Res 68:512,521, 2007. © 2008 Wiley-Liss, Inc. [source] Effects of clinical isolates of Pseudomonas aeruginosa on Staphylococcus epidermidis biofilm formationFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2010Maria Pihl Abstract Pseudomonas aeruginosa is often found in chronic infections, including cystic fibrosis lung infections and those related to chronic wounds and venous ulcers. At the latter sites, P. aeruginosa can be isolated together with Staphylococcus epidermidis, and we have therefore explored the effect of clinical isolates and laboratory strains of P. aeruginosa strains on colonization by S. epidermidis in dual-species biofilms. Biofilm formation was assayed using 16S rRNA FISH and confocal laser scanning microscopy. Among the six P. aeruginosa strains tested, one particular strain, denoted 14:2, exerted a significant inhibitory effect, and even after 6 h, S. epidermidis levels in dual-species biofilms were reduced by >85% compared with those without P. aeruginosa. Interestingly, strain 14:2 was found to be negative for classical virulence determinants including pyocyanin, elastase and alkaline protease. Therefore, we suggest that less virulent phenotypes of P. aeruginosa, which may develop over time in chronic infections, could counteract colonization by S. epidermidis, ensuring persistence and dominance by P. aeruginosa in the host micro-habitat. Further studies are required to explain the inhibitory effect on S. epidermidis, although extracellular polysaccharides produced by P. aeruginosa might play a role in this phenomenon. [source] DNA vaccines against chronic lung infections by Pseudomonas aeruginosaFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2-3 2003J Staczek Abstract Vaccines containing outer membrane protein F (OprF) of Pseudomonas aeruginosa are effective in reducing lesion severity in a mouse pulmonary chronic infection model. One OprF-based vaccine, called F/I, contains carboxy oprF sequences fused to oprI in an expression vector. When delivered three times biolistically by gene gun, the F/I vaccine induces protection that is antibody-mediated in outbred mice. To demonstrate the role of F/I -induced antibody-mediated immunity, B-cell-deficient [B(,)] and B-cell-intact [B(+)] mice were immunized with F/I, challenged with Pseudomonas, and examined for lesion severity. As expected, F/I -immunized B(+) mice had fewer and less severe lesions than vector-immunized B(+) mice. However, surprisingly, F/I - and vector-immunized B(,) mice were equally protected to levels similar to F/I -immunized B(+) mice. Examination of immune cell populations and cytokine levels indicated a relative increase in the quantity of CD3+ T-lymphocytes in vector- or F/I -immunized and challenged B(,) mice compared to B(+) mice. These data indicate the protective role played by cell-mediated immunity in B(,) mice, which supports our hypothesis that cell-mediated immunity can play an important role in protection against P. aeruginosa. [source] Immunisation with non-integral OMPs promotes pulmonary clearance of Pseudomonas aeruginosaFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2-3 2003Linda D. Thomas Abstract Pseudomonas aeruginosa is an opportunistic bacterial pathogen that can cause fatal acute lung infections in critically ill individuals. Lung damage due to chronic infections in cystic fibrosis sufferers is the major cause of morbidity and mortality in this group. The bacterium produces various immunomodulatory products that enable it to survive in the lung. Innate and increasing resistance to antibiotic therapy shown by this organism heightens the need for development of a vaccine. This study reports the identification of six non-integral protein antigens; Pa 13, azurin, acyl carrier protein (ACP), amidase, aminopeptidase and KatE, purified from a mucoid strain of P. aeruginosa. N-terminal amino acid sequencing was used to identify these proteins and, based on their ascribed functions, determined that their normal cellular location was cytosolic. A rat model of acute pulmonary infection was used to investigate the ability of these protein antigens to enhance pulmonary clearance of a live P. aeruginosa challenge. Mucosal immunisation with four of the six antigens significantly enhanced bacterial clearance from both the lavage fluid and lung tissue. The greatest level of clearance was demonstrated for the antigens; KatE, aminopeptidase and amidase. Enhanced bacterial clearance was maintained when the antigens amidase and aminopeptidase were produced in recombinant form. When delivered parenterally, aminopeptidase demonstrated its continued efficacy as a vaccine candidate. This study has demonstrated that non-integral outer membrane proteins are antigenic and protective and warrant further investigation as potential components of a vaccine. [source] Alcohol Stimulates Ciliary Motility of Isolated Airway Axonemes Through a Nitric Oxide, Cyclase, and Cyclic Nucleotide-Dependent Kinase MechanismALCOHOLISM, Issue 4 2009Joseph H. Sisson Background:, Lung mucociliary clearance provides the first line of defense from lung infections and is impaired in individuals who consume heavy amounts of alcohol. Previous studies have demonstrated that this alcohol-induced ciliary dysfunction occurs through impairment of nitric oxide (NO) and cyclic nucleotide-dependent kinase-signaling pathways in lung airway ciliated epithelial cells. Recent studies have established that all key elements of this alcohol-driven signaling pathway co-localize to the apical surface of the ciliated cells with the basal bodies. These findings led us to hypothesize that alcohol activates the cilia stimulation pathway at the organelle level. To test this hypothesis we performed experiments exposing isolated demembranated cilia (isolated axonemes) to alcohol and studied the effect of alcohol-stimulated ciliary motility on the pathways involved with isolated axoneme activation. Methods:, Isolated demembranated cilia were prepared from bovine trachea and activated with adenosine triphosphate. Ciliary beat frequency, NO production, adenylyl and guanylyl cyclase activities, cAMP- and cGMP-dependent kinase activities were measured following exposure to biologically relevant concentrations of alcohol. Results:, Alcohol rapidly stimulated axoneme beating 40% above baseline at very low concentrations of alcohol (1 to 10 mM). This activation was specific to ethanol, required the synthesis of NO, the activation of soluble adenylyl cyclase (sAC), and the activation of both cAMP- and cGMP-dependent kinases (PKA and PKG), all of which were present in the isolated organelle preparation. Conclusions:, Alcohol rapidly and sequentially activates the eNOS,NO,GC,cGMP,PKG and sAC,cAMP, PKA dual signaling pathways in isolated airway axonemes. These findings indicate a direct effect of alcohol on airway cilia organelle function and fully recapitulate the alcohol-driven activation of cilia known to exist in vivo and in intact lung ciliated cells in vitro following brief moderate alcohol exposure. Furthermore, these findings indicate that airway cilia are exquisitely sensitive to the effects of alcohol and substantiate a key role for alcohol in the alterations of mucociliary clearance associated with even low levels of alcohol intake. We speculate that this same axoneme-based alcohol activation pathway is down regulated following long-term high alcohol exposure and that the isolated axoneme preparation provides an excellent model for studying the mechanism of alcohol-mediated cilia dysfunction. [source] A Recent Perspective on Alcohol, Immunity, and Host DefenseALCOHOLISM, Issue 2 2009Gyongyi Szabo Background:, Multiple line of clinical and experimental evidence demonstrates that both acute, moderate, and chronic, excessive alcohol use result in various abnormalities in the functions of the immune system. Methods:, Medline and Pubmed databases were used to identify published reports with particular interest in the period of 2000,2008 in the subject of alcohol use, infection, inflammation, innate, and adaptive immunity. Results:, This review article summarizes recent findings relevant to acute or chronic alcohol use-induced immunomodulation and its consequences on host defense against microbial pathogens and tissue injury. Studies with in vivo and in vitro alcohol administration are both discussed. The effects of alcohol on lung infections, trauma and burn injury, liver, pancreas, and cardiovascular diseases are evaluated with respect to the role of immune cells. Specific changes in innate immune response and abnormalities in adaptive immunity caused by alcohol intake are detailed. Conclusion:, Altered inflammatory cell and adaptive immune responses after alcohol consumption result in increased incidence and poor outcome of infections and other organ-specific immune-mediated effects. [source] Hyper IgE (Job's) syndrome: a primary immune deficiency with oral manifestationsORAL DISEASES, Issue 1 2009AF Freeman Autosomal dominant hyper IgE (HIES or Job's) syndrome is a rare primary immune deficiency characterized by eczema, recurrent skin and lung infections, extremely elevated serum IgE, and a variety of connective tissue and skeletal abnormalities. Individuals with HIES share a characteristic facial appearance and many oral manifestations including retained primary dentition, a high arched palate, variations of the oral mucosa and gingiva, and recurrent oral candidiasis. Mutations in STAT3 account for the majority, if not all, of the cases of autosomal dominant HIES, but the pathogenesis of the many varied features remains poorly understood. In this review, we discuss the clinical phenotype of HIES including immunologic and non-immunologic features, the genetics of HIES, and treatment. [source] Novel intraoral phenotypes in hyperimmunoglobulin-E syndromeORAL DISEASES, Issue 1 2008DL Domingo Aim:, Hyperimmunoglobulin-E syndrome (HIES) is a primary immunodeficiency characterized by eczema, recurrent skin and lung infections with pneumatocoele formation, and extremely elevated serum immunoglobulin-E. The precise immunologic defect and genetic etiology remain unknown. Non-immunologic findings include characteristic facial features (prominent forehead, fleshy nasal tip, and increased interalar distance); skeletal involvement (pathological fractures, scoliosis, and craniosynostosis); and retention of primary teeth. This study aims to characterize intraoral soft tissue findings in HIES patients. Methods:, Sixty HIES patients (4,54 years, 27 males, 33 females) received intraoral and radiographic evaluations. Chronological dental development was also assessed. Results:, Lesions of the hard palate and dorsal tongue were found in 55% and 60% of patients, respectively. Palatal lesions ranged from a generalized surface keratosis to a midline sagittal fibrotic bridge. Tongue lesions consisted of multiple fissures and a midline cleft. On the lip and buccal mucosa, keratotic plaques and/or surface fissures were found in 8% and 23% of patients, respectively. Manifested in 76.7% of patients, the intraoral lesions were significantly more prevalent than the characteristic facial traits (P = 0.0013). Conclusions:, Alterations in oral mucosa and gingiva were present in the majority of HIES patients. These novel intraoral findings may facilitate the diagnosis of HIES. [source] Novel tobramycin inhalation powder in cystic fibrosis subjects: Pharmacokinetics and safetyPEDIATRIC PULMONOLOGY, Issue 4 2007David E. Geller MD Abstract Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy. We evaluated the pharmacokinetics (PK) and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections. This was a multi-center, open-label, sequential-cohort, single-dose, dose-escalation study using the standard 300 mg dose of tobramycin solution for inhalation (TSI) as an active control. Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts. Measurements included serum and sputum tobramycin concentrations, administration time, serum chemistries, acute change in lung function, and adverse events (AEs). Out of 90 randomized subjects, 86 had data for safety analysis; and 84 had data for PK analysis. Serum tobramycin PK profiles were similar for TIP and TSI. Four capsules of 28 mg TIP (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg TSI, in less than one-third the administration time. The most common AEs associated with TIP were cough (20%) and dysgeusia (17%). TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation. The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation. The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections. Pediatr Pulmonol. 2007; 42:307,313. © 2007 Wiley-Liss, Inc. [source] Preemptive Therapy for Systemic and Pulmonary Human Cytomegalovirus Infection in Lung Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009G. Gerna The incidence and treatment of both systemic and pulmonary human cytomegalovirus (HCMV) infection as well as HCMV-specific T-cell immune responses were investigated in 57 consecutive lung transplant recipients (LTR) by using as cutoffs for preemptive therapy: 300 000 DNA copies/mL whole blood for systemic infections and 100 000 DNA copies/mL bronchoalveolar lavage fluid for lung infections. Results showed that out of 29/57 LTR (50.9%) needing preemptive antiviral therapy, 15 (51.7%) reached the blood cutoff, 8 (27.6%) the pulmonary cutoff and 6 (20.7%) both the blood and the lung cutoff (3 simultaneously and 3 subsequently). Recovery of HCMV-specific T-cell immune responses was achieved much earlier for CD8+ than CD4+ T cells. However, protection from HCMV reactivation was conferred by the presence of both arms of the T-cell response. In two LTR reaching the pulmonary cutoff and not preemptively treated, a full HCMV-specific CD4+ and CD8+ T-cell response was associated with resolution of lung infection. Antirejection steroid therapy suppressed T-cell immune responses, thus facilitating HCMV reactivation. In conclusion, in LTR, monitoring HCMV infection in both blood and lungs, may improve preemptive therapy efficacy. In addition, monitoring the HCMV-specific T-cell immune response appears useful for predicting control of HCMV infection in the posttransplant period. [source] Influence of biofilm formation in the susceptibility of Pseudomonas aeruginosa from Brazilian patients with cystic fibrosisAPMIS, Issue 8 2010ALEX GUERRA FERREIRA Ferreira AG, Leão RS, Carvalho-Assef APD, Folescu TW, Barth AL, Marques EA. Influence of biofilm formation in the susceptibility of Pseudomonas aeruginosa from Brazilian patients with cystic fibrosis. APMIS 2010; 118: 606,12. Biofilms play a key role in the occurrence of lung infections by Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In this study, we examined 40 isolates of P. aeruginosa from CF patients according to their capacity to form biofilm. We also compared their in vitro response to antimicrobials according to different modes of growth (planktonic vs biofilm) and performed molecular typing. All isolates proved capable of forming biofilm. However, there was no difference in biofilm development according to the mucoid and nonmucoid phenotypes and among isolates obtained at different periods of the chronic infection. All isolates tested for antimicrobial susceptibility in the biofilm state (BIC) were consistently more resistant to antibiotics than the same isolate tested in the planktonic state. The molecular typing indicates a considerable clonal diversity among isolates. We identified five patients harboring the same strain over different periods. These strains, however, displayed different levels of biofilm formation and BIC values for antibiotics tested. The results of the present study demonstrate that there is a marked difference in the susceptibility profile according to the mode of growth of CF P. aeruginosa, as cells tested in the biofilm state proved consistently more resistant to antibiotics. [source] Cloning, expression, purification, crystallization and preliminary crystallographic studies of BceC, a UDP-glucose dehydrogenase from Burkholderia cepacia IST408ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010Joana Rocha Bacteria of the Burkholderia cepacia complex (Bcc) have emerged as important opportunistic pathogens, establishing lung infections in immunocompromised or cystic fibrosis patients. Bcc uses polysaccharide-biofilm production in order to evade the host immune response. The biofilm precursor UDP-glucuronic acid is produced by a twofold NAD+ -dependent oxidation of UDP-glucose. In B. cepacia IST408 this enzymatic reaction is performed by the UDP-glucose dehydrogenase BceC, a 470-residue enzyme, the production and crystallization of which are described here. The crystals belonged to the orthorhombic space group P212121 and contained four molecules in the asymmetric unit. Their crystallographic analysis at 2.09,Å resolution and a molecular-replacement study are reported. [source] Antibiotic-resistant obligate anaerobes during exacerbations of cystic fibrosis patientsCLINICAL MICROBIOLOGY AND INFECTION, Issue 5 2009D. Worlitzsch Abstract Pseudomonas aeruginosa and Staphylococcus aureus are thought to cause the majority of lung infections in patients with cystic fibrosis (CF). However, other bacterial pathogens may contribute to the pathophysiology of lung disease. Here, obligate anaerobes were identified in a cross-sectional study, and cell numbers and antibiotic susceptibilities of facultative and obligate anaerobes from 114 sputum samples from nine children and 36 adults with CF were determined. Furthermore, in 12 CF patients, we investigated whether conventional intravenous antibiotic therapy, administered during acute exacerbations, would affect the numbers of obligate anaerobes. Fifteen genera of obligate anaerobes were identified in 91% of the CF patients. Cell numbers (mean: 2.2 × 107 ± standard deviation 6.9 × 107 CFU/mL of sputum sample) were comparable to those of P. aeruginosa and S. aureus. Staphylococcus saccharolyticus and Peptostreptococcus prevotii were most prevalent. Infection with P. aeruginosa did not increase the likelihood that obligate anaerobes are present in sputum specimens. Single obligate anaerobic species persisted for up to 11 months in sputum plugs in vivo. Patients with and without obligate anaerobes in sputum specimens did not differ in lung function. Intravenous therapy directed against P. aeruginosa during acute exacerbations increased lung function, but did not reduce the numbers of obligate anaerobes. Obligate anaerobic species differed widely in their patterns of resistance against meropenem, piperacillin,tazobactam, clindamycin, metronidazole and ceftazidime. In 58% of patients with acute exacerbations, obligate anaerobes were detected that were resistant to the antibiotics used for treatment. Antibiotic therapy, optimized to target anaerobes in addition to P. aeruginosa, may improve the management of CF lung disease. [source] | ||||||||||