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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 August 2017, Vol.114(32), pp.E6632-E6641
    Description: Biofilms formed by nontypeable (NTHI) are central to the chronicity, recurrence, and resistance to treatment of multiple human respiratory tract diseases including otitis media, chronic rhinosinusitis, and exacerbations of both cystic fibrosis and chronic obstructive pulmonary disease. Extracellular DNA (eDNA) and associated DNABII proteins are essential to the overall architecture and structural integrity of biofilms formed by NTHI and all other bacterial pathogens tested to date. Although cell lysis and outer-membrane vesicle extrusion are possible means by which these canonically intracellular components might be released into the extracellular environment for incorporation into the biofilm matrix, we hypothesized that NTHI additionally used a mechanism of active DNA release. Herein, we describe a mechanism whereby DNA and associated DNABII proteins transit from the bacterial cytoplasm to the periplasm via an inner-membrane pore complex (TraC and TraG) with homology to type IV secretion-like systems. These components exit the bacterial cell through the ComE pore through which the NTHI type IV pilus is expressed. The described mechanism is independent of explosive cell lysis or cell death, and the release of DNA is confined to a discrete subpolar location, which suggests a novel form of DNA release from viable NTHI. Identification of the mechanisms and determination of the kinetics by which critical biofilm matrix-stabilizing components are released will aid in the design of novel biofilm-targeted therapeutic and preventative strategies for diseases caused by NTHI and many other human pathogens known to integrate eDNA and DNABII proteins into their biofilm matrix.
    Keywords: Hu ; Ihf ; Tra ; Edna ; Secretin ; Bacterial Proteins -- Metabolism ; DNA, Bacterial -- Metabolism ; DNA-Binding Proteins -- Metabolism ; Haemophilus Influenzae -- Metabolism ; Type IV Secretion Systems -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(6), p.e40088
    Description: Otitis media (OM) is a polymicrobial disease wherein prior or concurrent infection with an upper respiratory tract virus plays an essential role, predisposing the middle ear to bacterial invasion. In episodes of acute bacterial OM, respiratory syncytial virus (RSV) is the most commonly isolated virus and thus serves as an important co-pathogen. Of the predominant bacterial agents of OM, the pathogenesis of disease due to Moraxella catarrhalis is the least well understood. Rigorous study of M. catarrhalis in the context of OM has been significantly hindered by lack of an animal model. To bridge this gap, we assessed whether co-infection of chinchillas with M. catarrhalis and RSV would facilitate ascension of M. catarrhalis from the nasopharynx into the middle ear. Chinchillas were challenged intranasally with M. catarrhalis followed 48 hours later by intranasal challenge with RSV. Within 7 days, 100% of nasopharynges were colonized with M. catarrhalis and homogenates of middle ear mucosa were also culture-positive. Moreover, within the middle ear space, the mucosa exhibited hemorrhagic foci, and a small volume of serosanguinous effusion was present in one of six ears. To improve upon this model, and based on epidemiologic data, nontypeable Haemophilus influenzae (NTHI) was included as an additional bacterial co-pathogen via intranasal administration four days before M. catarrhalis challenge. With this latter protocol, M. catarrhalis was cultured from the nasopharynx and middle ear homogenates of a maximum of 88% and 79% animals, respectively, for up to 17 days after intranasal challenge with M. catarrhalis . Additionally, hemorrhagic foci were observed in 79% of middle ears upon sacrifice. Thus, these data demonstrated that co-infection with RSV and NTHI predisposed to M. catarrhalis -induced ascending experimental OM. This model can be used both in studies of pathogenesis as well as to investigate strategies to prevent or treat OM due to M. catarrhalis .
    Keywords: Research Article ; Biology ; Medicine ; Virology ; Infectious Diseases ; Microbiology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Journal of AOAC International, 2012, Vol.95(5), pp.1386-91
    Description: To improve throughput during peak seasonal demand, a screening method for the determination of fertilizer-available phosphate using a discrete analyzer for semi-automation was validated in a single laboratory. The fertilizer materials were extracted using a neutral EDTA-ammonium citrate solution as detailed...
    Keywords: Chemistry Techniques, Analytical -- Methods ; Fertilizers -- Analysis ; Phosphates -- Chemistry
    ISSN: 1060-3271
    E-ISSN: 19447922
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e67629
    Description: Cystic fibrosis (CF) is the most common lethal inherited genetic disorder affection Caucasians. Even with medical advances, CF is life-shortening with patients typically surviving only to age 38. Infection of the CF lung by Burkholderia cenocepacia presents exceptional challenges to medical management of these patients as clinically this microbe is resistant to virtually all antibiotics, is highly transmissible and infection of CF patients with this microbe renders them ineligible for lung transplant, often the last lifesaving option. Here we have targeted two abundant components of the B. cenocepacia biofilm for immune intervention: extracellular DNA and DNABII proteins, the latter of which are bacterial nucleic acid binding proteins. Treatment of B. cenocepacia biofilms with antiserum directed at one of these DNABII proteins (integration host factor or IHF) resulted in significant disruption of the biofilm. Moreover, when anti-IHF mediated destabilization of a B. cenocepacia biofilm was combined with exposure to traditional antibiotics, B. cenocepacia resident within the biofilm and thereby typically highly resistant to the action of antibiotics, were now rendered susceptible to killing. Pre-incubation of B. cenocepacia with anti-IHF serum prior to exposure to murine CF macrophages, which are normally unable to effectively degrade ingested B. cenocepacia, resulted in a statistically significant increase in killing of phagocytized B. cenocepacia. Collectively, these findings support further development of strategies that target DNABII proteins as a novel approach for treatment of CF patients, particularly those whose lungs are infected with B. cenocepacia.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    In: Molecular Microbiology, September 2014, Vol.93(6), pp.1246-1258
    Description: The extracellular polymeric substance produced by many human pathogens during biofilm formation often contains extracellular (). Strands of bacterial within the biofilm matrix can occur in a lattice‐like network wherein a member of the family of ‐binding proteins is positioned at the vertex of each crossed strand. To date, treatment of all biofilms tested with antibodies directed against one protein, ntegration ost actor (), results in significant disruption. Here, using non‐typeable as a model organism, we report that this effect was rapid, ‐specific and mediated by binding of transiently dissociated by anti‐ even when physically separated from the biofilm by a nucleopore membrane. Further, biofilm disruption fostered killing of resident bacteria by previously ineffective antibiotics. We propose the mechanism of action to be the sequestration of upon dissociation from the biofilm , forcing an equilibrium shift and ultimately, collapse of the biofilm. Further, antibodies against a peptide positioned at the ‐binding tips of were as effective as antibodies directed against the native protein. As incorporating and associated proteins is a common strategy for biofilms formed by multiple human pathogens, this novel therapeutic approach is likely to have broad utility.
    Keywords: Binding Proteins – Analysis ; Protein Binding – Analysis;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(2), p.e90505
    Description: Surface structures in Haemophilus influenzae are subject to rapid ON/OFF switching of expression, a process termed phase variation. We analyse tetranucleotide repeats controlling phase variation in lipo-oligosaccharide (LOS) genes of H. influenzae in paired isolates from both the nasopharynx and middle ears of paediatric patients with chronic or recurrent otitis media. A change in expression of at least one of the seven phase variable LOS biosynthesis genes was seen in 12 of the 21 strain pairs. Several strains showed switching of expression in multiple LOS genes, consistent with a key role for phase variable LOS biosynthetic genes in human infection.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: Cellular Microbiology, August 2016, Vol.18(8), pp.1043-1055
    Description: Nontypeable (NTHI) utilizes the Type IV pilus (Tfp) to adhere to respiratory tract epithelial cells thus colonizing its human host; however, the host cell receptor to which this adhesive protein binds is unknown. From a panel of receptors engaged by Tfp expressed by other bacterial species, we showed that the majority subunit of NTHI Tfp, PilA, bound to intercellular adhesion molecule 1 (ICAM1) and that this interaction was both specific and of high affinity. Further, Tfp‐expressing NTHI inoculated on to polarized respiratory tract epithelial cells that expressed ICAM1 were significantly more adherent compared to Tfp‐deficient NTHI or NTHI inoculated on to epithelial cells to which ICAM1 gene expression was silenced. Moreover, pre‐incubation of epithelial cells with recombinant soluble PilA (rsPilA) blocked adherence of NTHI, an outcome that was abrogated by admixing rsPilA with ICAM1 prior to application on to the target cells. Epithelial cells infected with adenovirus or respiratory syncytial virus showed increased expression of ICAM1; this outcome supported augmented adherence of Tfp‐expressing NTHI. Collectively, these data revealed the cognate receptor for NTHI Tfp as ICAM1 and promote continued development of a Tfp‐targeted vaccine for NTHI‐induced diseases of the airway wherein upper respiratory tract viruses play a key predisposing role. Nontypeable (NTHI) utilize Type IV pili (Tfp) for adherence to airway epithelial cells, shown herein to be mediated via engagement with ICAM1. Adherence of Tfp‐expressing NTHI was abrogated by pre‐incubation of airway cells with recombinant PilA protein or by silencing ICAM1 gene expression. Upper respiratory tract viral infection induced greater expression of ICAM1 by airway cells and further augmented NTHI adherence; thus promoting continued development of Tfp‐targeted vaccines for NTHI‐induced diseases wherein respiratory tract viruses play a role.
    Keywords: Pila Protein ; Gene Expression ; Respiratory Tract Diseases ; Epithelial Cells ; Data Processing ; Pili ; Intercellular Adhesion Molecule 1 ; Vaccines ; Infection ; Cell Adhesion ; Respiratory Tract ; Respiratory Syncytial Virus ; Haemophilus Influenzae ; Adenovirus ; Methods ; Methods ; Cell Biology;
    ISSN: 1462-5814
    E-ISSN: 1462-5822
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  • 8
    Language: English
    In: Trends in Microbiology, August 2018, Vol.26(8), pp.727-728
    Description: In this infographic the diseases caused by nontypeable (NTHi), including otitis media, are discussed. Encapsulated type b (Hib) was responsible for most of the invasive disease (meningitis) prior to the use of Hib vaccines. As Hib vaccines have no effect on infections due to nontypeable (NTHi), in areas where Hib vaccines are used, nontypeable strains are now the most common cause of invasive disease. Moreover, NTHi contributes to the ∼21 000 otitis media (OM)-associated deaths per year. Due to this collective global morbidity and mortality, concerted vaccine development is underway. In addition to preventing disease, an effective vaccine will likely help to mitigate the global crisis of antibiotic resistance. Since 1973, ampicillin resistance due to NTHi’s production of β-lactamase has been recognized; however, a significant concern is the more recent emergence and spread of β-lactamase-negative-ampicillin-resistant (BLNAR) strains in many regions of the world. As such, is one of 12 bacterial pathogens that are considered priority pathogens by the World Health Organization.
    Keywords: Biology
    ISSN: 0966-842X
    E-ISSN: 1878-4380
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  • 9
    Language: English
    In: Vaccine, 25 July 2013, Vol.31(34), pp.3417-3426
    Description: ► Transcutaneous immunization with chimV4+ dmLT resolved ongoing NTHI-induced experimental OM. ► Significant reduction in signs of OM, NTHI concentration and mucosal biofilms in the middle ear was achieved. ► Activated DCs, polyfunctional T-cells and host defense peptide contributed to rapid resolution. ► Immunogen-specific IgG in middle ear fluids also contributed to eradication of NTHI. ► Transcutaneous immunization is a simple strategy to induce efficacious immune responses. Transcutaneous immunization (TCI) is a simple and needle-free method with which to induce protective immune responses. Using a chinchilla model of nontypeable (NTHI)-induced otitis media (OM), we examined the efficacy afforded by TCI with a novel chimeric immunogen called ‘chimV4’ which targets two critical adhesins expressed by NTHI, outer membrane protein P5 and the majority subunit of NTHI Type IV pilus, PilA. Experimental OM was first established in cohorts of animals, and then TCI performed via a therapeutic immunization regime by rubbing vaccine formulations on hydrated pinnae. The kinetics of resolution of established experimental disease was evaluated by clinically-relevant assessments of OM, bacterial culture of planktonic and adherent NTHI within the middle ear and gross examination of the relative amount of NTHI mucosal biofilms within the middle ear space. Within seven days after primary TCI, a significant reduction in the signs of OM, significantly fewer NTHI adherent to the middle ear mucosa and significant resolution of mucosal biofilms was detected in animals that received chimV4+ the adjuvant LT(R192G-L211A), compared to animals administered LT(R192G-L211A) alone or saline by TCI ( 〈 0.05) with eradication of NTHI within an additional seven days. The mechanism for rapid disease resolution involved efflux of activated dermal dendritic cells from the pinnae after TCI, secretion of factors chemotactic for CD4 T-cells, induction of polyfunctional IFNγ- and IL-17-producing CD4 T-cells and secretion of host defense peptide within the middle ear. These data support TCI as a therapeutic intervention against experimental NTHI-induced OM and begin to elucidate the host response to immunization by this noninvasive regimen.
    Keywords: Chimv4 ; Omp P5 ; Type IV Pilus ; Chinchilla ; Mucosal Biofilm ; Dendritic Cell ; Dmlt ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 10
    Language: English
    In: Clinical and vaccine immunology : CVI, August 2015, Vol.22(8), pp.867-74
    Description: Transcutaneous immunization (TCI) is a noninvasive strategy to induce protective immune responses. We describe TCI with a band-aid vaccine placed on the postauricular skin to exploit the unique organization of the stratum corneum and to promote the development of immune responses to resolve active experimental otitis media due to nontypeable Haemophilus influenzae (NTHI). This therapeutic immunization strategy induced significantly earlier resolution of middle ear fluid and rapid eradication of both planktonic and mucosal biofilm-resident NTHI within 7 days after receipt of the first immunizing band-aid vaccine. Efficacy was ascribed to the homing of immunogen-bearing cutaneous dendritic cells to the nasal-associated lymphoid tissue, induction of polyfunctional CD4(+) T cells, and the presence of immunogen-specific IgM and IgG within the middle ear. TCI using band-aid vaccines could expand the use of traditional parenteral preventative vaccines to include treatment of active otitis media, in addition to other diseases of the respiratory tract due to NTHI.
    Keywords: Haemophilus Infections -- Therapy ; Immunization -- Methods ; Otitis Media -- Therapy
    E-ISSN: 1556-679X
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