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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 10 June 2016, Vol.291(24), pp.12538-46
    Description: Biofilms are organized multicellular communities encased in an extracellular polymeric substance (EPS). Biofilm-resident bacteria resist immunity and antimicrobials. The EPS provides structural stability and presents a barrier; however, a complete understanding of how EPS structure relates to biological function is lacking. This review focuses on the EPS of three Gram-negative pathogens: Pseudomonas aeruginosa, nontypeable Haemophilus influenzae, and Salmonella enterica serovar Typhi/Typhimurium. Although EPS proteins and polysaccharides are diverse, common constituents include extracellular DNA, DNABII (DNA binding and bending) proteins, pili, flagella, and outer membrane vesicles. The EPS biochemistry promotes recalcitrance and informs the design of therapies to reduce or eliminate biofilm burden.
    Keywords: Dnabii ; Haemophilus Influenzae ; Pseudomonas Aeruginosa ; Salmonella ; Animal Models ; Bacterial Pathogenesis ; Biofilm ; Edna ; Extracellular Matrix ; Matrix ; Neutrophil ; Phagocyte ; Pilin ; Polysaccharide ; Bacterial Infections -- Microbiology ; Biofilms -- Growth & Development ; DNA, Bacterial -- Metabolism ; Extracellular Matrix -- Metabolism ; Gram-Negative Bacteria -- Physiology ; Polysaccharides, Bacterial -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: Journal of Bacteriology, May, 2011, Vol.193(9-10), p.2527(9)
    Description: Bacterial strategies of innate immune evasion and essential metabolic functions are critical for commensalhost homeostasis. Previously, we showed that Sap translocator function is necessary for nontypeable Haemophilus influenzae (NTHI) behaviors that mediate diseases of the human airway. Antimicrobial peptide (AP) lethality is limited by binding mediated by the Sap complex. SapA shares homology with the dipeptide-binding protein (DppA) and the heme-binding lipoprotein (HbpA), both of which have previously been shown to bind the iron-containing compound heme, whose acquisition is essential for Haemophilus survival. Computational modeling revealed conserved SapA residues, similarly modeled to mediate heme binding in HbpA. Here, we directly demonstrate that SapA bound heme and was essential for heme utilization by iron-starved NTHI. Further, the Sap translocator permease mediated heme transport into the bacterial cytoplasm, thus defining a heretofore unknown mechanism of intracytoplasmic membrane heme transport in Haemophilus. Since we demonstrate multiple ligand specificity for the SapA-binding protein, we tested whether APs would compete with heme for SapA binding. We showed that human [beta]-defensins 2 and 3, human cathelicidin LL-37, human neutrophil protein 1, and melittin displaced heme bound to SapA, thus supporting a hierarchy wherein immune evasion supercedes even the needed iron acquisition functions of the Sap system. doi: 10.1128/JB.01313-10
    Keywords: Haemophilus Influenzae -- Physiological Aspects ; Haemophilus Influenzae -- Genetic Aspects ; Heme -- Physiological Aspects ; Heme -- Genetic Aspects
    ISSN: 0021-9193
    Source: Cengage Learning, Inc.
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  • 3
    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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  • 4
    Language: English
    In: Journal of Bacteriology, Nov, 2013, Vol.195(21-22), p.5102(10)
    Description: Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite very high vaccine coverage, pertussis has reemerged as a serious threat in the United States and many developing countries. Thus, it is important to pursue research to discover unknown pathogenic mechanisms of B. pertussis. We have investigated a previously uncharacterized locus in B. pertussis, the dra locus, which is homologous to the dlt operons of Gram-positive bacteria. The absence of the dra locus resulted in increased sensitivity to the killing action of antimicrobial peptides (AMPs) and human phagocytes. Compared to the wild-type cells, the mutant cells bound higher levels of cationic proteins and peptides, suggesting that dra contributes to AMP resistance by decreasing the electronegativity of the cell surface. The presence of dra led to the incorporation of d-alanine into an outer membrane component that is susceptible to proteinase K cleavage. We conclude that dra encodes a virulence-associated determinant and contributes to the immune resistance of B. pertussis. With these findings, we have identified a new mechanism of surface modification in B. pertussis which may also be relevant in other Gram-negative pathogens.
    Keywords: Bordetella Pertussis -- Research ; Bordetella Pertussis -- Physiological Aspects ; Alanine -- Influence ; Antimicrobial Peptides -- Research ; Neutrophils -- Research
    ISSN: 0021-9193
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: Journal of Bacteriology, April, 2012, Vol.194(7-8), p.1927(7)
    Description: We previously demonstrated that one or more products of the genes in the pil and com gene clusters of the opportunistic human respiratory pathogen nontypeable Haemophilus influenzae (NTHI) are required for type IV pilus (Tfp) biogenesis and function. Here, we have now demonstrated that the pilABCD and comABCDEF gene clusters are operons and that the product of each gene is essential for normal pilus function. Mutants with nonpolar deletions in each of the 10 pil and com genes had an adherence defect when primary human airway cells were used as the target. These mutants were also diminished in their ability to form a biofilm in vitro and, additionally, were deficient in natural transformation. Collectively, our data demonstrate that the product of each gene within these operons is required for the normal biogenesis and/or function of NTHI Tfp. Based on the similarity of PilA to other type IV pilins, we further predicted that the product of the pilA gene would be the major pilin subunit. Toward that end, we also demonstrated by immunogold labeling and mass spectrometry that PilA is indeed the majority type IV pilin protein expressed by NTHI. These new observations set the stage for experiments designed to dissect the function of each of the proteins encoded by genes within the pil and com gene clusters. The ability to characterize individual proteins with vital roles in NTHI colonization or pathogenesis has the potential to reduce the burden of NTHI-induced diseases through development of a Tfp-derived vaccine or a pilus-directed therapeutic.
    Keywords: Bacterial Genetics -- Research ; Gene Expression -- Research ; Haemophilus Influenzae -- Genetic Aspects ; Operons -- Research
    ISSN: 0021-9193
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: PLoS ONE, 01 October 2010, Vol.5(10), p.e13224
    Description: Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: The Journal of infectious diseases, 15 August 2015, Vol.212(4), pp.645-53
    Description: Hia is a major adhesin of nontypeable Haemophilus influenzae (NTHi) and has long been investigated as a vaccine candidate. Here we show that Hia phase variation is controlled by changes in the length of a polythymidine tract located in the hia promoter. Studies of an invasive clinical isolate (strain R2866) show that strains expressing high Hia levels are more efficiently killed by opsonophagocytosis. An opsonophagocytic assay was used to select for a subpopulation of variants that expressed a low level of Hia, which facilitated their escape from killing by anti-Hia antisera. Conversely, a subpopulation of variants expressing a high level of Hia was selected for during passaging through Chang cells. In both cases, phase variation of Hia expression corresponded directly with discrete modal changes in polythymidine tract length. In the chinchilla model of NTHi infection, we observed consistent selection for high Hia expression upon nasopharyngeal colonization, confirming the key role of phase-variable expression of Hia within a specific niche in vivo.
    Keywords: Haemophilus ; Adhesion ; Colonization ; Phase Variation ; Adhesins, Bacterial -- Metabolism ; Gene Expression Regulation, Bacterial -- Physiology ; Haemophilus Infections -- Microbiology ; Haemophilus Influenzae -- Classification
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 8
    Language: English
    In: Journal of bacteriology, 01 October 2016, Vol.198(19), pp.2619-30
    Description: Nontypeable Haemophilus influenzae (NTHI), a commensal of the human nasopharynx (hNP), is a common cause of biofilm-associated diseases of the respiratory tract. However, NTHI biofilm biology at the average hNP temperature, i.e., 34°C, has not been well studied. Here we grew NTHI biofilms at 34°C and 37°C, to evaluate relative biofilm growth, expression, and function of the type IV pilus (Tfp), a critical adhesin important for NTHI biofilm formation. The kinetics and regulation of Tfp expression in NTHI biofilms are unclear, especially at 34°C. Tfp expression, as estimated by pilA promoter activity, was distributed throughout the biofilms, with a unique pattern that was dependent on temperature, time in culture, and position within the maturing biofilm. Tfp expression was required for the formation of the characteristic tower structures of NTHI biofilms and was significantly upregulated in NTHI biofilms formed at 34°C versus 37°C. This increase correlated with significantly greater twitching motility at 34°C than at 37°C. Treatment with antisera targeting the major subunit of Tfp (PilA) significantly inhibited NTHI biofilm formation at both temperatures, confirming the importance of this critical adhesin in biofilm formation. Additionally, treatment of preestablished biofilms with antisera against PilA significantly decreased biofilm biomass and mean thickness at both temperatures. These results demonstrated a pivotal role for Tfp in NTHI biofilm formation and stability at the temperature of the hNP, and they underscore the utility of PilA as a vaccine candidate for treatment and/or prevention of NTHI biofilm-associated diseases. NTHI is an important cause of chronic respiratory tract infections, including otitis media, chronic rhinosinusitis, and exacerbations of chronic obstructive pulmonary disease and cystic fibrosis. The chronic and recurrent nature of these diseases is attributed to the presence of bacterial biofilms, which are highly resistant to antimicrobials. We characterized NTHI biofilm growth and expression of PilA, the major subunit of the Tfp, at the temperature of the hNP, which is the commensal habitat of NTHI. Our results expand the current understanding of the role of Tfp during biofilm formation and maturation at the temperature of both the hNP and the middle ear, and they strengthen support for PilA as a vaccine candidate for the prevention and treatment of NTHI biofilm-associated diseases.
    Keywords: Temperature ; Biofilms -- Growth & Development ; Fimbriae, Bacterial -- Metabolism ; Haemophilus Influenzae -- Classification ; Nasopharynx -- Physiology
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 9
    In: Molecular Microbiology, June 2015, Vol.96(6), pp.1119-1135
    Description: Most chronic and recurrent bacterial infections involve a biofilm component, the foundation of which is the extracellular polymeric substance (). Extracellular (e) is a conserved and key component of the of pathogenic biofilms. The protein family includes integration host factor () and histone‐like protein (); both are present in the extracellular milieu. We have shown previously that the proteins are often found in association with e and are critical for the structural integrity of bacterial communities that utilize e as a matrix component. Here, we demonstrate that uropathogenic () strain 89 incorporates e within its biofilm matrix and that the proteins are not only important for biofilm growth, but are limiting; exogenous addition of these proteins promotes biofilm formation that is dependent on e. In addition, we show that both subunits of , yet only one subunit of (), are critical for biofilm development. We discuss the roles of these proteins in context of the . Uropathogenic (UPEC) strain UTI89 incorporates eDNA within its biofilm matrix and that the DNABII proteins are not only important for biofilm growth, but are limiting; exogenous addition of these proteins promotes biofilm formation that is dependent on eDNA.
    Keywords: Biology;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 10
    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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