RESUMEN
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) was suggested as an entity separate from other types of Hodgkin lymphoma 40 years ago and recognized in the WHO classification in 2001. Based on its relatively benign course with late distant relapses, relation with lymph node hyperplasia with progressively transformed germinal centers, presence of clonal immunoglobulin gene rearrangements with somatic hypermutations and ongoing mutations, and relation with a number of inherited defects affecting the immune system, it has been suspected that NLPHL might be antigen-driven. Recent evidence has shown that cases of IgD-positive NLPHL are associated with infection by Moraxella catarrhalis, a common bacterium in the upper respiratory tract and in lymph nodes. This review summarizes the evidence for NLPHL as a B-cell lymphoma involving follicular T-lymphocytes normally found in germinal centers, its molecular features and relation to inherited immune defects, and its relation and differential diagnosis from similar entities. Finally, it discusses the evidence that in many cases a watch and wait policy might be a viable initial management strategy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Enfermedad de Hodgkin/inmunología , Moraxella catarrhalis/inmunología , Infecciones por Moraxellaceae/inmunología , Linfocitos T/inmunología , Antígenos de Neoplasias/genética , Linfocitos B/microbiología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/microbiología , Enfermedad de Hodgkin/terapia , Humanos , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/microbiología , Fenotipo , Pronóstico , Linfocitos T/microbiología , Microambiente TumoralRESUMEN
Some children are more susceptible to viral and bacterial respiratory infections in the first few years of life than others. However, the factors contributing to this susceptibility are incompletely understood. In a retrospective analysis of clinical samples collected from a prospectively-enrolled cohort of 358 children we sought associations between physician-attended illness visits and bacterial colonization in the first five years of life. A subset of children was identified by unsupervised clustering analysis as infection and allergy prone (IAP). Several respiratory infection- and allergy-mediated illnesses co-occurred at higher rates in IAP children, while the rates of other illnesses were not significantly different between the groups. Analyses of nasopharyngeal (NP) pathobionts and microbiota commensals showed that early age of first colonization with pathobionts Streptococcus pneumonia, non-typeable Haemophilus influenzae, and Moraxella catarrhalis was associated with IAP children, and particularly Moraxella abundance was negatively associated with NP microbiome diversity. We conclude that mucosal pathobiont exposures in early life can influence susceptibility to respiratory illnesses in children.
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Portador Sano/epidemiología , Enfermedades Nasofaríngeas/epidemiología , Neumonía Neumocócica/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Portador Sano/microbiología , Niño , Preescolar , Femenino , Haemophilus influenzae/aislamiento & purificación , Haemophilus influenzae/patogenicidad , Humanos , Lactante , Masculino , Microbiota , Moraxella catarrhalis/aislamiento & purificación , Moraxella catarrhalis/patogenicidad , Enfermedades Nasofaríngeas/microbiología , Nasofaringe/microbiología , Nasofaringe/patología , Neumonía Neumocócica/microbiología , Infecciones del Sistema Respiratorio/microbiología , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/patogenicidad , Streptococcus pneumoniae/aislamiento & purificación , Streptococcus pneumoniae/patogenicidadRESUMEN
Moraxella catarrhalis, Streptococcus pneumoniae, and nontypeable Haemophilus influenzae (NTHi) are ubiquitous upper respiratory opportunistic pathogens. Together, these three microbes are the most common causative bacterial agents of pediatric otitis media (OM) and have therefore been characterized as the primary human otopathogens. OM is the most prevalent bacterial infection in children and the primary reason for antibiotic administration in this population. Moreover, biofilm formation has been confirmed as a primary mechanism of chronic and recurrent OM disease. As bacterial biofilms are inherently metabolically recalcitrant to most antibiotics and these complex structures also present a significant challenge to the immune system, there is a clear need to identify novel antimicrobial approaches to treat OM infections. In this study, we evaluated the potential efficacy of antibacterial photodynamic therapy (aPDT) with the photosensitizer chlorin e6 (Ce6) against planktonic as well as biofilm-associated M. catarrhalis, S. pneumoniae, and NTHi. Our data indicate aPDT with Ce6 elicits significant bactericidal activity against both planktonic cultures and established biofilms formed by the three major otopathogens (with an efficacy of ≥99.9% loss of viability). Notably, the implementation of a novel, dual-treatment aPDT protocol resulted in this disinfectant effect on biofilm-associated bacteria and, importantly, inhibited bacterial regrowth 24 h posttreatment. Taken together, these data suggest this novel Ce6-aPDT treatment may be a powerful and innovative therapeutic strategy to effectively treat and eradicate bacterial OM infections and, significantly, prevent the development of recurrent disease.IMPORTANCE Otitis media (OM), or middle ear disease, is the most prevalent bacterial infection in children and the primary reason for antibiotic use and surgical intervention in the pediatric population. Biofilm formation by the major bacterial otopathogens, Moraxella catarrhalis, Streptococcus pneumoniae, and nontypeable Haemophilus influenzae, has been shown to occur within the middle ears of OM patients and is a key factor in the development of recurrent disease, which may result in hearing impairment and developmental delays. Bacterial biofilms are inherently impervious to most antibiotics and present a significant challenge to the immune system. In this study, we demonstrate that antimicrobial photodynamic therapy (aPDT) using the photosensitizer chlorin e6 elicits significant bactericidal activity versus planktonic and biofilm-associated otopathogens and supports further analyses of this novel, efficacious, and promising technology as an adjunctive treatment for acute and recurrent OM.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Otitis Media/microbiología , Fotoquimioterapia , Porfirinas/farmacología , Bacterias/clasificación , Bacterias/patogenicidad , Clorofilidas , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/patogenicidad , Humanos , Viabilidad Microbiana/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/patogenicidad , Otitis Media/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidadRESUMEN
We aimed to explore the role of TLR4 (rs4986790) polymorphism in the nasopharyngeal (NP) bacterial colonization and its consequent impact on the development of childhood asthma. A semi-quantitative culture of NP swabs was performed on 473 children at 2 months of age and on 213 children at 13 months of age. TLR4 polymorphism was analyzed for 396 children. Children were followed from birth to the age of 7.5 years and the final outcome was physician-diagnosed asthma. The associations between TLR4 genotype, bacterial colonization, and asthma were analyzed. Children with TLR4 AG or GG genotype were more often colonized with Moraxella catarrhalis at 2 months of age (p = 0.009) and Haemophilus influenzae at 13 months of age (p = 0.018). Children who were colonized with H. influenzae at 13 months of age had a significantly higher risk of later development of asthma (p = 0.004). M. catarrhalis or H. Influenzae colonization at 2 months of age or TLR4 genotype Asp299Gly were not associated with the development of childhood asthma. TLR4 Asp299Gly polymorphism was associated with an increased risk of colonization of M. catarrhalis and H. influenzae in children. The colonization with H. influenzae at 13 months of age was associated with a higher risk of later development of childhood asthma.
Asunto(s)
Asma/genética , Infecciones por Haemophilus/genética , Infecciones por Moraxellaceae/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 4/genética , Asma/epidemiología , Asma/patología , Niño , Preescolar , Femenino , Infecciones por Haemophilus/epidemiología , Infecciones por Haemophilus/patología , Haemophilus influenzae/patogenicidad , Humanos , Lactante , Masculino , Microbiota , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/epidemiología , Infecciones por Moraxellaceae/patología , Cavidad Nasal/microbiología , Faringe/microbiologíaRESUMEN
Moraxella catarrhalis is a human-adapted, opportunistic bacterial pathogen of the respiratory mucosa. Although asymptomatic colonization of the nasopharynx is common, M. catarrhalis can ascend into the middle ear, where it is a prevalent causative agent of otitis media in children, or enter the lower respiratory tract, where it is associated with acute exacerbations of chronic obstructive pulmonary disease in adults. Phase variation is the high frequency, random, reversible switching of gene expression that allows bacteria to adapt to different host microenvironments and evade host defences, and is most commonly mediated by simple DNA sequence repeats. Bioinformatic analysis of five closed M. catarrhalis genomes identified 17 unique simple DNA sequence repeat tracts that were variable between strains, indicating the potential to mediate phase variable expression of the associated genes. Assays designed to assess simple sequence repeat variation under conditions mimicking host infection demonstrated that phase variation of uspA1 (ubiquitous surface protein A1) from high to low expression occurs over 72 hours of biofilm passage, while phase variation of uspA2 (ubiquitous surface protein A2) to high expression variants occurs during repeated exposure to human serum, as measured by mRNA levels. We also identify and confirm the variable expression of two novel phase variable genes encoding a Type III DNA methyltransferase (modO), and a conserved hypothetical permease (MC25239_RS00020). These data reveal the repertoire of phase variable genes mediated by simple sequence repeats in M. catarrhalis and demonstrate that modulation of expression under conditions mimicking human infection is attributed to changes in simple sequence repeat length.
Asunto(s)
Regulación Bacteriana de la Expresión Génica/genética , Moraxella catarrhalis/genética , Adhesión Bacteriana/genética , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Expresión Génica/genética , Humanos , Repeticiones de Microsatélite/genética , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae , Otitis Media/microbiología , Secuencias Repetitivas de Ácidos Nucleicos/genéticaRESUMEN
All infective bacterial species need to conquer the innate immune system in order to colonize and survive in their hosts. The human respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis are no exceptions and have developed sophisticated mechanisms to evade complement-mediated killing. Both bacterial species carry lipooligosaccharides preventing complement attacks and attract and utilize host complement regulators C4b binding protein and factor H to inhibit the classical and alternative pathways of complement activation, respectively. In addition, the regulator of the terminal pathway of complement activation, vitronectin, is hijacked by both bacteria. An array of different outer membrane proteins (OMP) in H. influenzae and M. catarrhalis simultaneously binds complement regulators, but also plasminogen. Several of the bacterial complement-binding proteins are important adhesins and contain highly conserved regions for interactions with the host. Thus, some of the OMP are viable targets for new therapeutics, including vaccines aimed at preventing respiratory tract diseases such as otitis media in children and exacerbations in patients suffering from chronic obstructive pulmonary disease.
Asunto(s)
Proteína de Unión al Complemento C4b/inmunología , Factor H de Complemento/inmunología , Infecciones por Haemophilus/inmunología , Haemophilus influenzae , Evasión Inmune , Moraxella catarrhalis , Infecciones por Moraxellaceae/inmunología , Infecciones del Sistema Respiratorio/inmunología , Animales , Proteínas de la Membrana Bacteriana Externa/inmunología , Infecciones por Haemophilus/patología , Haemophilus influenzae/inmunología , Haemophilus influenzae/patogenicidad , Humanos , Moraxella catarrhalis/inmunología , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/patología , Otitis Media/inmunología , Otitis Media/patología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , Infecciones del Sistema Respiratorio/patologíaRESUMEN
INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare genetically heterogeneous disorder of motile cilia, which leads to recurrent and chronic airway infections. Detailed information about infection causing pathogens is scarce. With this study, we aimed to determine the prevalence and susceptibility of the most common respiratory pathogens in PCD patients retrospectively in a cross-sectional and the dynamics of the microbiological diversity in a longitudinal study. METHODS: Microbiological and clinical data of 106 patients between 2010 and 2016 were analysed cross-sectionally and of 28 patients longitudinally. Dynamics in microbiological diversity were assessed by calculating the mean rate of alteration (MRA). RESULTS: Haemophilus influenzae was the most common pathogen (nâ¯=â¯41; 38.7%) followed by Staphylococcus aureus (nâ¯=â¯36; 34%), Moraxella catarrhalis (nâ¯=â¯18; 17%) and Pseudomonas aeruginosa (nâ¯=â¯16; 15.1%). Nontuberculous mycobacteria were cultured from two patients (1.9%). H. influenzae was the most prevalent pathogen in children (nâ¯=â¯31; 45.6%), S. aureus in adults (nâ¯=â¯15; 39%). Two patients were infected by methicillin-resistant S. aureus. P. aeruginosa was mostly susceptible to standard antibiotics with highest rates of resistance against fosfomycin (63.6%; 7/11). The culture of P. aeruginosa correlated negatively with age adjusted FEV1% predicted (pâ¯=â¯0.04), while the MRA was positively associated with age (rho 0.411, pâ¯=â¯0.032). DISCUSSION: In PCD patients, the prevalence of pathogens differed in children and adults with H. influenzae and S. aureus being the most common pathogens in children, S. aureus and P. aeruginosa in adults, respectively. Unexpectedly, the MRA increased by age.
Asunto(s)
Trastornos de la Motilidad Ciliar/microbiología , Haemophilus influenzae/patogenicidad , Moraxella catarrhalis/patogenicidad , Sistema Respiratorio/microbiología , Staphylococcus aureus/patogenicidad , Adulto , Niño , Trastornos de la Motilidad Ciliar/complicaciones , Estudios Transversales , Haemophilus influenzae/aislamiento & purificación , Humanos , Moraxella catarrhalis/aislamiento & purificación , Recurrencia , Infecciones del Sistema Respiratorio/etiología , Estudios Retrospectivos , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
BACKGROUND: Empiric antibiotics are administered for pneumonia when the causative pathogens are unidentified. Pathogen-directed therapy is impeded by negative culture results and/or culture time lag. This circumstance necessitates a salvage method for pathogen identification, especially when antibiotic therapy has failed. Here, we aimed to preliminarily investigate the HIRA-TAN method in pneumonia with a progressive course despite prior empiric antibiotic therapy. METHODS: This prospective study was conducted for patients who were referred to Dr. Zainoel Abidin Hospital, Aceh, Indonesia, from December 2016 to January 2017, owing to pneumonia with a progressive course. Sputum or pleural effusion was subjected to culture and the HIRA-TAN assay. The HIRA-TAN identified the candidate causative pathogens based on the difference in the cycle threshold (Ct) between the targeted pathogen and the single-copy human gene. RESULTS: Patients (n=27) were predominantly males (22 patients, 81.5%), with a median age of 62 years. All patients had comorbid disease and were classified as hospital-acquired pneumonia (25 patients, 92.6%) with multilobar infiltrates (22 patients, 81.5%). Bacterial culture identified causative pathogen(s) in some (14 patients, 51.8%), whereas the HIRA-TAN identified pathogen(s) in most (23 patients, 85.2%). The rapid pathogen identification by the HIRA-TAN will provide valuable information in guiding pathogen-directed therapy. CONCLUSIONS: The result warrants a larger clinical trial to confirm the clinical efficacy of the HIRA-TAN in patients with progressive pneumonia despite previous antibiotic treatment.
Asunto(s)
Antibacterianos/uso terapéutico , Neumonía Asociada a la Atención Médica/tratamiento farmacológico , Neumonía Asociada a la Atención Médica/microbiología , Klebsiella pneumoniae/aislamiento & purificación , Moraxella catarrhalis/aislamiento & purificación , Pseudomonas aeruginosa/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Streptococcus pneumoniae/aislamiento & purificación , Progresión de la Enfermedad , Femenino , Humanos , Klebsiella pneumoniae/patogenicidad , Masculino , Persona de Mediana Edad , Moraxella catarrhalis/patogenicidad , Estudios Prospectivos , Pseudomonas aeruginosa/patogenicidad , Streptococcus pneumoniae/patogenicidad , Insuficiencia del TratamientoRESUMEN
The most frequent ailment for which antibiotics are prescribed is otitis media (ear infections), which is most commonly caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae Treatment of otitis media is complicated by the fact that the bacteria in the middle ear typically form biofilms, which can be recalcitrant to antibiotic treatment. Furthermore, bacterial respiratory infections can be greatly exacerbated by viral coinfection, which is particularly evidenced by the synergy between influenza and S. pneumoniae In this study, we sought to ascertain the in vivo efficacy of aminomethyl spectinomycin lead 1950, an effective antibacterial agent both in vitro and in vivo against Streptococcus pneumoniae in the context of complex respiratory infections and acute otitis media. A single dose of 1950 significantly reduced bacterial burden in the respiratory tract for all three pathogens, even when species were present in a coinfection model. Additionally, a single dose of 1950 effectively reduced pneumococcal acute otitis media from the middle ear. The agent 1950 also proved efficacious in the context of influenza-pneumococcal super infection. These data further support the development of this family of compounds as potential therapeutic agents against the common causes of complex upper respiratory tract infections and acute otitis media.
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Infecciones del Sistema Respiratorio/tratamiento farmacológico , Espectinomicina/uso terapéutico , Animales , Femenino , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/patogenicidad , Ratones , Ratones Endogámicos BALB C , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/patogenicidad , Otitis Media/tratamiento farmacológico , Otitis Media/microbiología , Neumonía/tratamiento farmacológico , Neumonía/microbiología , Espectinomicina/administración & dosificación , Espectinomicina/química , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidadRESUMEN
BACKGROUND: Persistence of bacterial pathogens in the airways has profound consequences on the course and pathogenesis of chronic obstructive pulmonary disease (COPD). Patients with COPD continuously acquire and clear strains of Moraxella catarrhalis, a major pathogen in COPD. Some strains are cleared quickly and some persist for months to years. The mechanism of the variability in duration of persistence is unknown. METHODS: Guided by genome sequences of selected strains, we studied the expression of Hag/MID, hag/mid gene sequences, adherence to human cells, and autoaggregation in longitudinally collected strains of M. catarrhalis from adults with COPD. RESULTS: Twenty-eight of 30 cleared strains of M. catarrhalis expressed Hag/MID whereas 17 of 30 persistent strains expressed Hag/MID upon acquisition by patients. All persistent strains ceased expression of Hag/MID during persistence. Expression of Hag/MID in human airways was regulated by slipped-strand mispairing. Virulence-associated phenotypes (adherence to human respiratory epithelial cells and autoaggregation) paralleled Hag/MID expression in airway isolates. CONCLUSIONS: Most strains of M. catarrhalis express Hag/MID upon acquisition by adults with COPD and all persistent strains shut off expression during persistence. These observations suggest that Hag/MID is important for initial colonization by M. catarrhalis and that cessation of expression facilitates persistence in COPD airways.
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Adhesinas Bacterianas/genética , Moraxella catarrhalis/genética , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/microbiología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Sistema Respiratorio/microbiología , Adulto , Adhesión Bacteriana , Expresión Génica , Humanos , Moraxella catarrhalis/fisiología , Fenotipo , Factores de Virulencia/genéticaRESUMEN
PURPOSE: Moraxella catarrhalis is implicated in the pathogenesis of some COPD exacerbations. We sought to investigate whether the M. catarrhalis strain is variable between COPD subjects; that an exacerbation is associated with acquisition of a new strain and that certain strains are more commonly associated with exacerbations. PATIENTS AND METHODS: Sputum samples were collected at stable and exacerbation visits from COPD subjects from a single center as part of the COPDMAP consortium. Samples identified as M. catarrhalis positive by qPCR were recultured in liquid cultures grown to extract genomic DNA; underwent Illumina MiSeq and bacterial genome sequences were de novo assembled and Multi Locus Sequence Type (MLST) was determined. RESULTS: Thirty-five samples were obtained from 18 subjects. These included 13 stable and 22 exacerbation samples. The diversity between samples was very large with 25 different M. catarrhalis MLSTs being identified out of the 35 samples of which 12 MSLTs have not been described previously. Change and persistence of M. catarrhalis strain were observed between stable visits, from stable to exacerbation and vice-a-versa, and between exacerbation visits. CONCLUSION: Sputum M. catarrhalis strains exhibit marked diversity within and between COPD subjects. Acquisition of a new strain is common between stable and exacerbation events such that no strain is specifically associated with an exacerbation.
Asunto(s)
ADN Bacteriano/genética , Pulmón/microbiología , Moraxella catarrhalis/genética , Infecciones por Moraxellaceae/microbiología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Infecciones del Sistema Respiratorio/microbiología , Esputo/microbiología , Anciano , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Moraxella catarrhalis/clasificación , Moraxella catarrhalis/aislamiento & purificación , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/diagnóstico , Infecciones por Moraxellaceae/fisiopatología , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/fisiopatologíaRESUMEN
Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa are common Gram-negative pathogens associated with an array of pulmonary diseases. All three species have multiple adhesins in their outer membrane, i.e. surface structures that confer the ability to bind to surrounding cells, proteins or tissues. This mini-review focuses on proteins with high affinity for the components of the extracellular matrix such as collagen, laminin, fibronectin and vitronectin. Adhesins are not structurally related and may be lipoproteins, transmembrane porins or large protruding trimeric auto-transporters. They enable bacteria to avoid being cleared together with mucus by attaching to patches of exposed extracellular matrix, or indirectly adhering to epithelial cells using matrix proteins as bridging molecules. As more adhesins are being unravelled, it is apparent that bacterial adhesion is a highly conserved mechanism, and that most adhesins target the same regions on the proteins of the extracellular matrix. The surface exposed adhesins are prime targets for new vaccines and the interactions between proteins are often possible to inhibit with interfering molecules, e.g heparin. In conclusion, this highly interesting research field of microbiology has unravelled host-pathogen interactions with high therapeutic potential.
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Adhesinas Bacterianas/inmunología , Adhesión Bacteriana , Proteínas de la Matriz Extracelular/inmunología , Bacterias Aerobias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/inmunología , Evasión Inmune , Pulmón/inmunología , Infecciones del Sistema Respiratorio/inmunología , Adhesinas Bacterianas/metabolismo , Animales , Proteínas de la Matriz Extracelular/metabolismo , Bacterias Aerobias Gramnegativas/metabolismo , Bacterias Aerobias Gramnegativas/patogenicidad , Infecciones por Bacterias Gramnegativas/metabolismo , Infecciones por Bacterias Gramnegativas/microbiología , Haemophilus influenzae/inmunología , Haemophilus influenzae/metabolismo , Haemophilus influenzae/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Pulmón/metabolismo , Pulmón/microbiología , Moraxella catarrhalis/inmunología , Moraxella catarrhalis/metabolismo , Moraxella catarrhalis/patogenicidad , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and the in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for Moraxella catarrhalis and Haemophilus influenzae DS-2969b was active against MRSA with an MIC90 of 0.25 µg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10-10 in all four S. aureus isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC (fTMIC) correlated best with in vivo efficacy, and the static percent fTMIC was 43 to 49%. A sufficient fTMIC was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.
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Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Profármacos/farmacología , Animales , Antibacterianos/uso terapéutico , Girasa de ADN/genética , Girasa de ADN/metabolismo , Femenino , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/enzimología , Haemophilus influenzae/patogenicidad , Staphylococcus aureus Resistente a Meticilina/enzimología , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/enzimología , Moraxella catarrhalis/patogenicidad , Neumonía Estafilocócica/tratamiento farmacológico , Neumonía Estafilocócica/microbiología , Profármacos/uso terapéutico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Staphylococcus aureus/patogenicidadRESUMEN
Malonyl-CoA:acyl carrier protein transacylase (FabD), being an essential enzyme of the FAS II pathway, is an attractive target for developing broad-spectrum antibiotics. It performs initiation reaction to form malonyl-ACP, which is a key building block in fatty acid biosynthesis. In this study, we have characterized the FabD from drug-resistant pathogen Moraxella catarrhalis (McFabD). More importantly, we have shown the binding of McFabD with three new compounds from the class of aporphine alkaloids. ITC based binding studies have shown that apomorphine is binding to McFabD with a stronger affinity (KDâ¯=â¯4.87 µM) as compared to boldine (KDâ¯=â¯7.19 µM) and magnoflorine (KDâ¯=â¯11.7 µM). The possible mechanism of fluorescence quenching is found to be static with Kq values higher than 1010, which was associated with the ground state complex formation of aporphine alkaloids with McFabD. Conformational changes observed in the secondary and tertiary structure marked by the loss of helical content during the course of interactions. Molecular docking based studies have predicted the binding mode of aporphine alkaloids and it is found that these compounds are interacting in a similar fashion as known inhibitor corytuberine is interacting with McFabD. The analysis of docking poses have revealed that His 210, Leu102, Gln19, Ser101 and Arg 126 are critical residues, which may play important role in binding. The growth inhibition assay has shown that apomorphine has better MIC value (4-8⯵g/ml) against Moraxella catarrhalis as compared to boldine and magnoflorine. Therefore, the current study suggests that aporphine alkaloids can act as antibacterial agents and possible target of these compounds could be FabD enzyme from the FAS II pathway, and apomorphine scaffold will be more suitable among these compounds for potential development of antibacterial agents.
Asunto(s)
S-Maloniltransferasa de la Proteína Transportadora de Grupos Acilo/química , Alcaloides/química , Aporfinas/química , Moraxella catarrhalis/química , Alcaloides/farmacología , Aporfinas/farmacología , Fenómenos Biofísicos , Simulación por Computador , Farmacorresistencia Microbiana/genética , Humanos , Simulación del Acoplamiento Molecular , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/crecimiento & desarrollo , Moraxella catarrhalis/patogenicidad , Unión Proteica , Transducción de Señal/efectos de los fármacosRESUMEN
Moraxella catarrhalis is a common human respiratory tract pathogen. Its virulence factors associated with whole bacteria or outer membrane vesicles (OMVs) aid infection, colonization and may induce specific antibodies. To investigate pathogen-host interactions, we applied integrated bioinformatic and immunoproteomic (2D-electrophoresis, immunoblotting, LC-MS/MS) approaches. We showed that OMV proteins engaged exclusively in complement evasion and colonization strategies, but not those involved in iron transport and metabolism, are major targets for cross-reacting antibodies produced against phylogenetically divergent M. catarrhalis strains. The analysis of 31 complete genomes of M. catarrhalis and other Moraxella revealed that OMV protein-coding genes belong to 64 orthologous groups, five of which are restricted to M. catarrhalis. This species showed a two-fold increase in the number of OMV protein-coding genes relative to its ancestors and animal-pathogenic Moraxella. The appearance of specific OMV factors and the increase in OMV-associated virulence proteins during M. catarrhalis evolution is an interesting example of pathogen adaptation to optimize colonization. This precisely targeted cross-reactive immunity against M. catarrhalis may be an important strategy of host defences to counteract this phenomenon. We demonstrate that cross-reactivity is closely associated with the anti-virulent antibody repertoire which we have linked with adaptation of this pathogen to the host.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Vesículas Extracelulares/inmunología , Moraxella catarrhalis/inmunología , Infecciones por Moraxellaceae/inmunología , Factores de Virulencia/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Pared Celular/inmunología , Pared Celular/metabolismo , Biología Computacional , Reacciones Cruzadas/inmunología , Modelos Animales de Enfermedad , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Genoma Bacteriano/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Moraxella catarrhalis/genética , Moraxella catarrhalis/metabolismo , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/sangre , Infecciones por Moraxellaceae/microbiología , Proteómica , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
Moraxella catarrhalis is a human-restricted opportunistic bacterial pathogen of the respiratory mucosa. It frequently colonizes the nasopharynx asymptomatically, but is also an important causative agent of otitis media (OM) in children, and plays a significant role in acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults. As the current treatment options for M. catarrhalis infection in OM and exacerbations of COPD are often ineffective, the development of an efficacious vaccine is warranted. However, no vaccine candidates for M. catarrhalis have progressed to clinical trials, and information regarding the distribution of M. catarrhalis virulence factors and vaccine candidates is inconsistent in the literature. It is largely unknown if virulence is associated with particular strains or subpopulations of M. catarrhalis, or if differences in clinical manifestation can be attributed to the heterogeneous expression of specific M. catarrhalis virulence factors in the circulating population. Further investigation of the distribution of M. catarrhalis virulence factors in the context of carriage and disease is required so that vaccine development may be targeted at relevant antigens that are conserved among disease-causing strains. The challenge of determining which of the proposed M. catarrhalis virulence factors are relevant to human disease is amplified by the lack of a standardized M. catarrhalis typing system to facilitate direct comparisons of worldwide isolates. Here we summarize and evaluate proposed relationships between M. catarrhalis subpopulations and specific virulence factors in the context of colonization and disease, as well as the current methods used to infer these associations.
Asunto(s)
Moraxella catarrhalis/inmunología , Moraxella catarrhalis/patogenicidad , Infecciones por Moraxellaceae/inmunología , Infecciones por Moraxellaceae/microbiología , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Humanos , Moraxella catarrhalis/clasificación , Moraxella catarrhalis/genética , Infecciones por Moraxellaceae/tratamiento farmacológico , Infecciones por Moraxellaceae/prevención & control , Otitis Media/tratamiento farmacológico , Otitis Media/inmunología , Otitis Media/microbiología , Otitis Media/prevención & control , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Enfermedad Pulmonar Obstructiva Crónica/prevención & control , Virulencia/genética , Virulencia/inmunología , Factores de Virulencia/genética , Factores de Virulencia/inmunologíaRESUMEN
Moraxella catarrhalis is a major cause of morbidity and mortality worldwide, especially causing otitis media in young children and exacerbations of chronic obstructive pulmonary disease in adults. This pathogen uses several virulence mechanisms to colonize and survive in its host, including adherence and invasion of host cells, formation of polymicrobial biofilms with other bacterial pathogens, and production of ß-lactamase. Given the global impact of otitis media and COPD, an effective vaccine to prevent M. catarrhalis infection would have a huge impact on the quality of life in both patient populations by preventing disease, thus reducing morbidity and health care costs. A number of promising vaccine antigens have been identified for M. catarrhalis. The development of improved animal models of M. catarrhalis disease and identification of a correlate of protection are needed to accelerate vaccine development. This review will discuss the current state of M. catarrhalis vaccine development, and the challenges that must be addressed to succeed.
Asunto(s)
Vacunas Bacterianas , Moraxella catarrhalis/inmunología , Infecciones por Moraxellaceae/prevención & control , Otitis Media/prevención & control , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Adulto , Animales , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/inmunología , Biopelículas , Niño , Modelos Animales de Enfermedad , Humanos , Ratones , Moraxella catarrhalis/patogenicidad , Otitis Media/economía , Otitis Media/microbiología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Calidad de Vida , Infecciones del Sistema Respiratorio/prevención & control , VirulenciaRESUMEN
BACKGROUND: We assessed nasopharyngeal (NP) carriage of five pathogens in febrile children with and without acute respiratory infection (ARI) of the upper (URTI) or lower tract, attending health facilities in Tanzania. METHODS: NP swabs collected from children (N = 960) aged 2 months to 10 years, and with a temperature ≥38°C, were utilized to quantify bacterial density of S. pneumoniae (Sp), H. influenzae (Hi), M. catarrhalis (Mc), S. aureus (Sa), and N. meningitidis (Nm). We determined associations between presence of individual species, densities, or concurrent carriage of all species combination with respiratory diseases including clinical pneumonia, pneumonia with normal chest radiography (CXR) and endpoint pneumonia. RESULTS: Individual carriage, and NP density, of Sp, Hi, or Mc, but not Sa, or Nm, was significantly associated with febrile ARI and clinical pneumonia when compared to febrile non-ARI episodes. Density was also significantly increased in severe pneumonia when compared to mild URTI (Sp, p<0.002; Hi p<0.001; Mc, p = 0.014). Accordingly, concurrent carriage of Sp+, Hi+, and Mc+, in the absence of Sa- and Nm-, was significantly more prevalent in children with ARI (p = 0.03), or clinical pneumonia (p<0.001) than non-ARI, and in children with clinical pneumonia (p = 0.0007) than URTI. Furthermore, Sp+, Hi+, and Mc+ differentiated children with pneumonia with normal CXR, or endpoint pneumonia, from those with URTI, and non-ARI cases. CONCLUSIONS: Concurrent NP carriage of Sp, Hi, and Mc was a predictor of clinical pneumonia and identified children with pneumonia with normal CXR and endpoint pneumonia from those with febrile URTI, or non-ARI episodes.
Asunto(s)
Haemophilus influenzae/patogenicidad , Moraxella catarrhalis/patogenicidad , Neumonía/diagnóstico , Streptococcus pneumoniae/patogenicidad , Niño , Preescolar , Femenino , Haemophilus influenzae/aislamiento & purificación , Humanos , Lactante , Recién Nacido , Masculino , Moraxella catarrhalis/aislamiento & purificación , Nasofaringe/microbiología , Nasofaringe/patología , Neumonía/epidemiología , Neumonía/microbiología , Neumonía/patología , Pronóstico , Streptococcus pneumoniae/aislamiento & purificación , TanzaníaRESUMEN
Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media (middle ear infections) in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In view of the huge global burden of disease caused by M. catarrhalis, the development of vaccines to prevent these infections and better approaches to treatment have become priorities. In previous work, we used a genome mining approach that identified three substrate binding proteins (SBPs) of ATP-binding cassette (ABC) transporters as promising candidate vaccine antigens. In the present study, we performed a comprehensive assessment of 19 SBPs of 15 ABC transporter systems in the M. catarrhalis genome by engineering knockout mutants and studying their role in assays that assess mechanisms of infection. The capacity of M. catarrhalis to survive and grow in the nutrient-limited and hostile environment of the human respiratory tract, including intracellular growth, account in part for its virulence. The results show that ABC transporters that mediate uptake of peptides, amino acids, cations and anions play important roles in pathogenesis by enabling M. catarrhalis to 1) grow in nutrient-limited conditions, 2) invade and survive in human respiratory epithelial cells and 3) persist in the lungs in a murine pulmonary clearance model. The knockout mutants of SBPs and ABC transporters showed different patterns of activity in the assay systems, supporting the conclusion that different SBPs and ABC transporters function at different stages in the pathogenesis of infection. These results indicate that ABC transporters are nutritional virulence factors, functioning to enable the survival of M catarrhalis in the diverse microenvironments of the respiratory tract. Based on the role of ABC transporters as virulence factors of M. catarrhalis, these molecules represent potential drug targets to eradicate the organism from the human respiratory tract.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas Bacterianas/metabolismo , Moraxella catarrhalis/metabolismo , Moraxella catarrhalis/patogenicidad , Infecciones del Sistema Respiratorio/metabolismo , Células A549 , Transportadoras de Casetes de Unión a ATP/genética , Animales , Proteínas Bacterianas/genética , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Genoma Bacteriano/genética , Humanos , Ratones Endogámicos BALB C , Sistema Respiratorio/metabolismo , Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/genética , VirulenciaRESUMEN
BACKGROUND: The effect of potentially pathogenic bacteria (PPB) on disease severity in patients with bronchiolitis is understudied. METHODS: This prospective study was carried out in the Children's Hospital of Soochow University during the 2012-2013 autumn and winter seasons. We enrolled consecutive children < 2 years of age hospitalized with an attending physician's diagnosis of bronchiolitis. Nasopharyngeal aspirate samples were tested for multiple respiratory viruses and cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. RESULTS: In all, 30% (188 patients) were positive for Strep. pneumoniae, H. influenzae, M. catarrhalis, and Staph. aureus. Length of stay (LOS) for patients with PPB was 4.0 days (interquartile range, IQR, 25th-75th percentile: 3.0-6.0 days) versus 3.0 days (IQR, 3.0-5.0 days) for patients without PPB (p < 0.001). However, requirement and duration of supplemental oxygen were not significantly different between the two groups. H. influenzae was an independent risk factor for hospital LOS ≥ 5.0 days (adjusted odds ratio, 1.75; 95% confidence interval, 1.06-2.91). The presence of PPB was not associated with increased risk of supplemental oxygen requirement. CONCLUSIONS: Our study demonstrated that pediatricians should evaluate for PPB in patients with bronchiolitis, especially when they present with RSV infection, fever or percentage of neutrophils > 40%. The presence of H. influenzae in nasal aspirates is associated with longer LOS in patients with bronchiolitis.