scholarly journals Lipooligosaccharides Containing Phosphorylcholine Delay Pulmonary Clearance of Nontypeable Haemophilus influenzae

2008 ◽  
Vol 76 (5) ◽  
pp. 2037-2043 ◽  
Author(s):  
Bing Pang ◽  
Dana Winn ◽  
Ryan Johnson ◽  
Wenzhou Hong ◽  
Shayla West-Barnette ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Bacterial Resistance ◽  
Serial Passage ◽  
Model Systems ◽  
Immunofluorescent Staining ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Nontypeable Haemophilus Influenzae ◽  
Bacterial Populations ◽  
Pulmonary Clearance

ABSTRACT Nontypeable Haemophilus influenzae (NTHi) causes pulmonary infections in patients with chronic obstructive pulmonary disease and other mucociliary clearance defects. Like many bacteria inhabiting mucosal surfaces, NTHi produces lipooligosaccharide (LOS) endotoxins that lack the O side chain. Persistent NTHi populations express a discrete subset of LOS glycoforms, including those containing phosphorylcholine (PCho). In this study, we compared two NTHi strains with isogenic mutants lacking PCho for clearance from mice following pulmonary infection. Consistent with data from other model systems, populations of the strains NTHi 2019 and NTHi 86-028NP recovered from mouse lung contained an increased proportion of PCho+ variants compared to that in the inocula. PCho− mutants were more rapidly cleared. Serial passage of NTHi increased both PCho content and bacterial resistance to clearance, and no such increases were observed for PCho− mutants. Increased PCho content was also observed in NTHi populations within non-endotoxin-responsive C3H/HeJ and Toll-like receptor 4 null (TLR4−/−) mice, albeit at later times postinfection. Changes in bacterial subpopulations and clearance were unaffected in TLR2−/− mice compared to the subpopulations in and clearance from mice of the parental strain. The clearance of PCho− mutants occurred at earlier time points in both strain backgrounds and in all types of mice. Comparison of bacterial populations in lung tissue cryosections by immunofluorescent staining showed sparse bacteria within the air spaces of C57BL/6 mice and large bacterial aggregates within the lungs of MyD88−/− mice. These results indicate that PCho promotes bacterial resistance to pulmonary clearance early in infection in a manner that is at least partially independent of the TLR4 pathway.

scholarly journals Diminished ICAM-1 Expression and Impaired Pulmonary Clearance of Nontypeable Haemophilus influenzae in a Mouse Model of Chronic Obstructive Pulmonary Disease/Emphysema

2008 ◽  
Vol 76 (11) ◽  
pp. 4959-4967 ◽  
Author(s):  
Bing Pang ◽  
Wenzhou Hong ◽  
Shayla L. West-Barnette ◽  
Nancy D. Kock ◽  
W. Edward Swords
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Haemophilus Influenzae ◽  
Pulmonary Disease ◽  
Intercellular Adhesion Molecule ◽  
Chronic Obstructive ◽  
Lung Pathology ◽  
Nontypeable Haemophilus Influenzae ◽  
Obstructive Pulmonary Disease ◽  
Pulmonary Clearance ◽  
Time Point

ABSTRACT The airways of patients with chronic obstructive pulmonary disease (COPD) are continually colonized with bacterial opportunists like nontypeable Haemophilus influenzae (NTHi), and a wealth of evidence indicates that changes in bacterial populations within the lung can influence the severity of COPD. In this study, we used a murine model for COPD/emphysema to test the hypothesis that COPD affects pulmonary clearance. Mice were treated with a pulmonary bolus of elastase, and as reported previously, the lungs of these mice were pathologically similar to those with COPD/emphysema at ∼1 month posttreatment. Pulmonary clearance of NTHi was significantly impaired in elastase-treated versus mock-treated mice. While histopathologic analysis revealed minimal differences in localized lung inflammation between the two groups, lower levels of intercellular adhesion molecule 1 (ICAM-1) were observed for the airway epithelial surface of elastase-treated mice than for those of control mice. Following infection, elastase-treated mice had lung pathology consistent with pneumonia for as long as 72 h postinfection, whereas at the same time point, mock-treated mice had cleared NTHi and showed little apparent pathology. Large aggregates of bacteria were observed within damaged lung tissue of the elastase-treated mice, whereas sparse individual bacteria were observed in lungs of mock-treated mice at the same time point postinfection. Additional infection studies showed that NTHi mutants with biofilm defects were less persistent in the elastase-treated mice than the parent strain. These findings establish a model for COPD-related infections and support the hypotheses that ICAM-1 promotes clearance of NTHi. Furthermore, the data indicate that NTHi may form biofilms within the context of COPD-related infections.

scholarly journals Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases

2017 ◽  
Vol 312 (5) ◽  
pp. L678-L687 ◽  
Author(s):  
Sandra Hodge ◽  
Hai B. Tran ◽  
Rhys Hamon ◽  
Eugene Roscioli ◽  
Greg Hodge ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Lung Diseases ◽  
Bacterial Resistance ◽  
Scavenger Receptor ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Apoptotic Cells ◽  
Nontypeable Haemophilus Influenzae ◽  
Pyrin Domain ◽  
Chronic Lung Diseases

We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides—2′-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2′-desoxy molecule (GS-560660)—with significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5–1 µg/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained >85% following 24 h exposure to either macrolide at concentrations up to 20 µg/ml. Secreted and intracellular-cleaved IL-1β was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll-like receptor 2/4; or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also reduced significantly. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance.

scholarly journals The MyD88-Dependent, but Not the MyD88-Independent, Pathway of TLR4 Signaling Is Important in Clearing Nontypeable Haemophilus influenzae from the Mouse Lung

2005 ◽  
Vol 175 (9) ◽  
pp. 6042-6049 ◽  
Author(s):  
Catharina W. Wieland ◽  
Sandrine Florquin ◽  
Nico A. Maris ◽  
Kasper Hoebe ◽  
Bruce Beutler ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Mouse Lung ◽  
Nontypeable Haemophilus Influenzae ◽  
Tlr4 Signaling

scholarly journals A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

2011 ◽  
Vol 79 (8) ◽  
pp. 3366-3376 ◽  
Author(s):  
Charles V. Rosadini ◽  
Jeffrey D. Gawronski ◽  
Daniel Raimunda ◽  
José M. Argüello ◽  
Brian J. Akerley
Keyword(s):  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Pathogen ◽  
Lung Infection ◽  
Lung Model ◽  
Mouse Lung ◽  
Infection Model ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
Lung Colonization

ABSTRACTNontypeableHaemophilus influenzae(NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence ofH. influenzae. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the “zinc bindingessential forvirulence” (zev) locus consisting ofzevA(HI1249) andzevB(HI1248). NTHI mutants ofzevAandzevBgrew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate thatzevABis a novel virulence factor important for zinc utilization ofH. influenzaeunder conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.

scholarly journals Characterization of igaB, a Second Immunoglobulin A1 Protease Gene in Nontypeable Haemophilus influenzae

2006 ◽  
Vol 74 (10) ◽  
pp. 5860-5870 ◽  
Author(s):  
Matthew M. Fernaays ◽  
Alan J. Lesse ◽  
Xueya Cai ◽  
Timothy F. Murphy
Keyword(s):  
Haemophilus Influenzae ◽  
Virulence Factor ◽  
Protease Activity ◽  
Geographic Origin ◽  
Respiratory Pathogen ◽  
Chronic Obstructive ◽  
Protease Gene ◽  
Nontypeable Haemophilus Influenzae ◽  
Potential Virulence Factor ◽  
Iga1 Protease

ABSTRACT Nontypeable Haemophilus influenzae is an important respiratory pathogen, causing otitis media in children and lower respiratory tract infection in adults with chronic obstructive pulmonary disease (COPD). Immunoglobulin A1 (IgA1) protease is a well-described protein and potential virulence factor in this organism as well as other respiratory pathogens. IgA1 proteases cleave human IgA1, are involved in invasion, and display immunomodulatory effects. We have identified a second IgA1 protease gene, igaB, in H. influenzae that is present in addition to the previously described IgA1 protease gene, iga. Reverse transcriptase PCR and IgA1 protease assays indicated that the gene is transcribed, expressed, and enzymatically active in H. influenzae. The product of this gene is a type 2 IgA1 protease with homology to the iga gene of Neisseria species. Mutants that were deficient in iga, igaB, and both genes were constructed in H. influenzae strain 11P6H, a strain isolated from a patient with COPD who was experiencing an exacerbation. Analysis of these mutants indicated that igaB is the primary mediator of IgA1 protease activity in this strain. IgA1 protease activity assays on 20 clinical isolates indicated that the igaB gene is associated with increased levels of IgA1 protease activity. Approximately one-third of 297 strains of H. influenzae of diverse clinical and geographic origin contained igaB. Significant differences in the prevalence of igaB were observed among isolates from different sites of isolation (sputum > middle ear > nasopharynx). These data support the hypothesis that the newly discovered igaB gene is a potential virulence factor in nontypeable H. influenzae.

scholarly journals Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

2015 ◽  
Vol 59 (5) ◽  
pp. 2700-2712 ◽  
Author(s):  
Begoña Euba ◽  
Javier Moleres ◽  
Cristina Viadas ◽  
Montserrat Barberán ◽  
Lucía Caballero ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Respiratory Infection ◽  
Opportunistic Pathogen ◽  
Lavage Fluid ◽  
Cellular Level ◽  
Chronic Obstructive ◽  
Therapeutic Effects ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACTNontypeableHaemophilus influenzae(NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.

scholarly journals Draft genome sequence of a nontypeable Haemophilus influenzae strain used in the study of human respiratory infection

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Rajendra KC ◽  
Ronan F. O’Toole
Keyword(s):  
Haemophilus Influenzae ◽  
Genome Sequence ◽  
Draft Genome ◽  
Subsequent Development ◽  
Laboratory Strain ◽  
Draft Genome Sequence ◽  
Chronic Obstructive ◽  
Nontypeable Haemophilus Influenzae ◽  
Obstructive Pulmonary Disease ◽  
Genome Data

Abstract Objectives Nontypeable Haemophilus influenzae (NTHi) is an important human respiratory bacterium that can cause a range of diseases including sinusitis, otitis media, conjunctivitis, pneumonia as well as acute exacerbations of chronic obstructive pulmonary disease (COPD). A number of studies have used NTHi clinical isolate RHH-3 as a laboratory strain for experimentation examining the effect of cigarette smoke and more recently, biomass smoke, on the susceptibility and response of cells lining the respiratory tract to infection. Therefore, definition of the genome content of RHH-3 is required to fully elucidate human-NTHi interactions associated with initial infection and subsequent development of respiratory disease. Data description Here, we present the draft genome sequence of NTHi RHH-3 collected from the sputum of a patient at the Royal Hobart Hospital, Tasmania, Australia. The assembled genome size was 1,839,376 bp consisting of 61 contigs (> 500 bp), with a G+C content of 38.1%. This draft genome data can be accessed at DDBJ/ENA/GenBank under the accession number JADPRR000000000.

scholarly journals Molecular Characterization of Fluoroquinolone Resistance in Nontypeable Haemophilus influenzae Clinical Isolates

2014 ◽  
Vol 59 (1) ◽  
pp. 461-466 ◽  
Author(s):  
Carmen Puig ◽  
José Manuel Tirado-Vélez ◽  
Laura Calatayud ◽  
Fe Tubau ◽  
Junkal Garmendia ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Nalidixic Acid ◽  
Respiratory Infections ◽  
Pulse Field ◽  
Fluoroquinolone Resistance ◽  
Chronic Obstructive ◽  
Nontypeable Haemophilus Influenzae ◽  
High Genetic Diversity ◽  
Content Type ◽  
Pulse Field Gel Electrophoresis

ABSTRACTNontypeableHaemophilus influenzae(NTHi) is a common cause of respiratory infections in adults, who are frequently treated with fluoroquinolones. The aims of this study were to characterize the genotypes of fluoroquinolone-resistant NTHi isolates and their mechanisms of resistance. Among 7,267H. influenzaeisolates collected from adult patients from 2000 to 2013, 28 (0.39%) were ciprofloxacin resistant according to Clinical and Laboratory Standards Institute (CLSI) criteria. In addition, a nalidixic acid screening during 2010 to 2013 detected five (0.23%) isolates that were ciprofloxacin susceptible but nalidixic acid resistant. Sequencing of their quinolone resistance-determining regions and genotyping by pulse-field gel electrophoresis and multilocus sequence typing of the 25 ciprofloxacin-resistant isolates available and all 5 nalidixic acid-resistant isolates were performed. In the NTHi isolates studied, two mutations producing changes in two GyrA residues (Ser84, Asp88) and/or two ParC residues (Ser84, Glu88) were associated with increased fluoroquinolone MICs. Strains with one or two mutations (n= 15) had ciprofloxacin and levofloxacin MICs of 0.12 to 2 μg/ml, while those with three or more mutations (n= 15) had MICs of 4 to 16 μg/ml. Long persistence of fluoroquinolone-resistant strains was observed in three chronic obstructive pulmonary disease patients. High genetic diversity was observed among fluoroquinolone-resistant NTHi isolates. Although fluoroquinolones are commonly used to treat respiratory infections, the proportion of resistant NTHi isolates remains low. The nalidixic acid disk test is useful for detecting the first changes in GyrA or in GyrA plus ParC among fluoroquinolone-susceptible strains that are at a potential risk for the development of resistance under selective pressure by fluoroquinolone treatment.

scholarly journals Closed Complete Genome Sequences of Two Nontypeable Haemophilus influenzae Strains Containing Novel modA Alleles from the Sputum of Patients with Chronic Obstructive Pulmonary Disease

2018 ◽  
Vol 7 (2) ◽  
Author(s):  
John M. Atack ◽  
Timothy F. Murphy ◽  
Lauren O. Bakaletz ◽  
Kate L. Seib ◽  
Michael P. Jennings
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Haemophilus Influenzae ◽  
Pulmonary Disease ◽  
Complete Genome ◽  
Chronic Obstructive ◽  
Phase Variable ◽  
Nontypeable Haemophilus Influenzae ◽  
Genome Sequences ◽  
Obstructive Pulmonary Disease ◽  
Content Type

Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen that causes otitis media and exacerbations of chronic obstructive pulmonary disease (COPD). Here, we report the complete genome sequences of NTHi strains 10P129H1 and 84P36H1, isolated from COPD patients, which contain the phase-variable epigenetic regulators ModA15 and ModA18, respectively.

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