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Gilad Bachrach - One of the best experts on this subject based on the ideXlab platform.
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Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives.
Frontiers in cellular and infection microbiology, 2017Co-Authors: Jawad Abed, Naseem Maalouf, Lishay Parhi, Stella Chaushu, Ofer Mandelboim, Gilad BachrachAbstract:Colorectal adenocarcinoma (CRC) is a common tumor with high mortality rates. Interestingly, CRC was found to be colonized by the oral anaerobic bacteria Fusobacterium nucleatum, which accelerates tumor progression and enables immune evasion. The CRC-specific colonization by Fusobacteria is mediated through the recognition of tumor displayed Gal-GalNAc moieties by the Fusobacterial Fap2 Gal-GalNAc lectin. Here, we show high Gal-GalNAc levels in additional adenocarcinomas including those found in the stomach, prostate, ovary, colon, uterus, pancreas, breast, lung and esophagus. This observation coincides with recent reports that found Fusobacterial DNA in some of these tumors. Given the tumorigenic role of Fusobacteria and its immune evasion properties, we suggest that Fusobacterial elimination might improve treatment outcome of the above tumors. Furthermore, as Fusobacteria appears to specifically home-in to Gal-GalNAc – displaying tumors, it might be engineered as a platform for treating CRC and the above common, lethal, adenocarcinomas.
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abstract 3300 gal galnac overexpressed in colorectal carcinoma mediates attachment and colonization of fusobacterium nucleatum utilizing the fap2 lectin
Cancer Research, 2016Co-Authors: Jawad Abed, Johanna Emgard, Stella Chaushu, Wendy S Garrett, Gilad BachrachAbstract:Recent reports revealed overabundance of oral Fusobacterium nucleatum (Fn) in colorectal carcinoma (CRC) compared to adjacent healthy tissue. This study aims to investigate the molecular mechanisms that mediate CRC colonization by Fn. Using the orthotopic Colon-26 colorectal cancer model, we found that intravascular injected Fn colonizes CRC more than adjacent healthy tissue. Fusobacterial localization in the colon is tumor-dependent, as injected Fusobacteria were undetected in the colons of tumor-free mice. CRC colonization is species specific as the gram-negative, anaerobe and periodontitis-related pathogen Prophyromonas gingivalis, which was shown to be abundant in oral tumors failed to colonize CRC. Higher levels of D-galactose-β(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) are known to be detected in CRC. We recently identified the Fusobacterial Fap2 outer-surface protein as a galactose binding lectin, suggesting that it might promote binding of Fusobacteria to CRC. A fluorescent-labeled Peanut Agglutinin lectin (PNA) detected more Gal-GalNAc in human and mouse CRC compared to adjacent healthy tissues. Binding of FITC-labeled Fn corresponded with the levels of Gal-GalNAc and colocalized with Gal-GalNAc in the tumor. Flow cytometry revealed that Fap2-deficient Fn mutants are impaired in binding to CRC cell lines compared with their WT parent. Soluble GalNAc inhibited the binding of PNA and WT Fn to CRC cells in a dose-dependent manner, but did not affect the residual CRC binding of fap2 mutated Fn. Furthermore, in the colorectal cancer murine model, tumor colonization by Fap2-deficient Fn mutants was significantly lower than that of the Fap2 sufficient parental strain. Our results demonstrate that the Fusobacterial Fap2 lectin binds to Gal-GalNAc on CRC and mediates the tumor-specific attachment of Fn. Understanding the interaction of Fn with CRC, may enable future development of novel diagnostic and therapeutic agents for this disease. Citation Format: Jawad H. Abed, Johanna Emgard, Stella Chaushu, Wendy Garrett, Gilad Bachrach. Gal-GalNAc overexpressed in colorectal carcinoma mediates attachment and colonization of Fusobacterium nucleatum utilizing the Fap2 lectin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3300.
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Messieurs, c'est les microbes qui auront le dernier mot": Gentlemen, it is the microbes who have the last word (Louis Pasteur)-Fusobacterium nucleatum protect tumors from killing by immune cells.
Oncoimmunology, 2015Co-Authors: Chamutal Gur, Ofer Mandelboim, Gilad BachrachAbstract:Fusobacterium nucleatum is present in colon cancers where it was shown to generate a proinflammatory microenvironment that supports colorectal neoplasia progression. Remarkably, alongside with proinflammatory stimulation, Fusobacteria also inhibit cytotoxicity of immune cells. Thus, it appears as if tumors exploit Fusobacteria to generate a favorable proinflammatory and anti-cytotoxic microenvironment.
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fap2 of fusobacterium nucleatum is a galactose inhibitable adhesin involved in coaggregation cell adhesion and preterm birth
Infection and Immunity, 2015Co-Authors: Shunit Coppenhagenglazer, Jawad Abed, R Naor, Gilad BachrachAbstract:ABSTRACT Fusobacterium nucleatum is a common oral anaerobe involved in periodontitis that is known to translocate and cause intrauterine infections. In the oral environment, F. nucleatum adheres to a large diversity of species, facilitating their colonization and creating biological bridges that stabilize the multispecies dental biofilm. Many of these interactions (called coadherences or coaggregations) are galactose sensitive. Galactose-sensitive interactions are also involved in the binding of F. nucleatum to host cells. Hemagglutination of some F. nucleatum strains is also galactose sensitive, suggesting that a single galactose-sensitive adhesin might mediate the interaction of Fusobacteria with many partners and targets. In order to identify the Fusobacterial galactose-sensitive adhesin, a system for transposon mutagenesis in Fusobacteria was created. The mutant library was screened for hemagglutination deficiency, and three clones were isolated. All three clones were found to harbor the transposon in the gene coding for the Fap2 outer membrane autotransporter. The three fap2 mutants failed to show galactose-inhibitable coaggregation with Porphyromonas gingivalis and were defective in cell binding. A fap2 mutant also showed a 2-log reduction in murine placental colonization compared to that of the wild type. Our results suggest that Fap2 is a galactose-sensitive hemagglutinin and adhesin that is likely to play a role in the virulence of Fusobacteria.
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Fusobacteria as a Bridge between Health and Disease: a Metatranscriptomic Approach
Oral Microbial Communities, 2011Co-Authors: Gilad Bachrach, Shunit Coppenhagen-glazer, Itamar SimonAbstract:Fusobacterium nucleatum is an oral anaerobe and the most common gram-negative isolate from both healthy and diseased oral sites. Association of F. nucleatum with gingivitis and with its progression to periodontal disease has been based on the fact that numbers of F. nucleatum organisms greatly increase in samples taken from diseased sites compared to those from healthy ones. The author feels that the sharing of both gram-positive and gram-negative properties might facilitate communication of Fusobacteria with both gram-positive early colonizers and gram-negative late colonizers, an essential stage in the development of the periopathogenic dental biofilm. The species complexity of oral biofilms is probably the greatest hurdle in studying the Fusobacterial role in oral health and disease. The author proposes that Fusobacterial virulence relies on the presence of its adhesins and not on classical toxins and proteases. Microarrays can be designed to interact uniquely with F. nucleatum gene transcripts. These microarrays can be reacted with total RNAs extracted from dental biofilms sampled from healthy and diseased periodontal sites of increasing disease severity. In vitro studies have suggested that Fusobacterial bridging coaggregation interactions are important for the shift in the composition of the microbial community associated with transition from health to disease. Ongoing introduction of tools for genetic manipulation of Fusobacteria will enable the investigation of Fusobacterial virulence-associated molecular elements. Integration species-specific and general molecular tools is expected to enable the study and the understanding of F. nucleatum's role in bridging from oral health to disease.
D.c.a. Robinson - One of the best experts on this subject based on the ideXlab platform.
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The infectious aetiology of tropical ulcer—a study of the role of anaerobic bacteria
British Journal of Dermatology, 2006Co-Authors: Beverley Adriaans, B S Drasar, D.c.a. RobinsonAbstract:SUMMARY We have cultured anaerobic bacteria from patients with tropical ulcers. Fusobacteria were isolated most frequently. Anaerobes were always present, together with aerobes or facultative anaerobes, particularly in early phase ulcers, suggesting that the combination of organisms is important in the pathogenesis of the disease. Spirochaetes were identified in material examined by light and electron microscopy, but were not cultured.
Chang Soo Eun - One of the best experts on this subject based on the ideXlab platform.
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role of Fusobacteria in the serrated pathway of colorectal carcinogenesis
Scientific Reports, 2016Co-Authors: Chan Hyuk Park, Dong Soo Han, Areum Lee, Yura Lee, Chang Soo EunAbstract:Fusobacteria are associated with colorectal cancer (CRC) and are amplified during colorectal carcinogenesis. Compared to the adenoma-carcinoma sequence of carcinogenesis, serrated neoplasm has distinct clinical features and a different molecular background. We aimed to compare the gut microbiome between tubular adenoma (TA) and sessile serrated adenoma/polyp (SSA/P). Patients with TA, SSA/P, or CRC were recruited. Three pieces of colorectal mucosal tissue were obtained from each patient by endoscopic biopsy. 16S rRNA gene pyrosequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) were performed. Among 26 enrolled patients, 8, 10, and 8 had TA, SSA/P, and CRC, respectively. The relative abundance of Fusobacteria did not differ significantly between the TA and SSA/P groups (4.3% and 1.9%, P = 0.739) but was higher in the CRC group (33.8%) than in the TA or SSA/P group, respectively (TA vs. CRC, P = 0.002, false discovery rate [FDR] = 0.023; SSA/P vs. CRC, P < 0.001, FDR = 0.001). PICRUSt revealed that most functions in the TA metagenome were similar to those in the SSA/P metagenome. The gut microbiome, including relative abundance of Fusobacteria, did not differ between TA and SSA/P, suggesting that Fusobacteria may contribute to both the serrated pathway and the adenoma-carcinoma sequence.
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Role of Fusobacteria in the serrated pathway of colorectal carcinogenesis
Scientific reports, 2016Co-Authors: Chan Hyuk Park, Dong Soo Han, Areum Lee, Yura Lee, Chang Soo EunAbstract:Fusobacteria are associated with colorectal cancer (CRC) and are amplified during colorectal carcinogenesis. Compared to the adenoma-carcinoma sequence of carcinogenesis, serrated neoplasm has distinct clinical features and a different molecular background. We aimed to compare the gut microbiome between tubular adenoma (TA) and sessile serrated adenoma/polyp (SSA/P). Patients with TA, SSA/P, or CRC were recruited. Three pieces of colorectal mucosal tissue were obtained from each patient by endoscopic biopsy. 16S rRNA gene pyrosequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) were performed. Among 26 enrolled patients, 8, 10, and 8 had TA, SSA/P, and CRC, respectively. The relative abundance of Fusobacteria did not differ significantly between the TA and SSA/P groups (4.3% and 1.9%, P = 0.739) but was higher in the CRC group (33.8%) than in the TA or SSA/P group, respectively (TA vs. CRC, P = 0.002, false discovery rate [FDR] = 0.023; SSA/P vs. CRC, P
Paul E. Kolenbrander - One of the best experts on this subject based on the ideXlab platform.
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fusobacterium nucleatum atcc 10953 requires actinomyces naeslundii atcc 43146 for growth on saliva in a three species community that includes streptococcus oralis 34
Applied and Environmental Microbiology, 2009Co-Authors: Saravanan Periasamy, Natalia I. Chalmers, Laurence Duthumm, Paul E. KolenbranderAbstract:Formation of dental plaque is a developmental process involving initial and late colonizing species that form polymicrobial communities. Fusobacteria are the most numerous gram-negative bacteria in dental plaque, but they become prevalent after the initial commensal colonizers, such as streptococci and actinomyces, have established communities. The unusual ability of these bacteria to coaggregate with commensals, as well as pathogenic late colonizers, has been proposed to facilitate colonization by the latter organisms. We investigated the integration of Fusobacterium nucleatum into multispecies communities by employing two in vitro models with saliva as the sole nutritional source. In flow cell biofilms, numbers of cells were quantified using fluorescently conjugated antibodies against each species, and static biofilms were analyzed by quantitative real-time PCR (q-PCR) using species-specific primers. Unable to grow as single-species biofilms, F. nucleatum grew in two-species biofilms with Actinomyces naeslundii but not with Streptococcus oralis. However, enhanced growth of Fusobacteria was observed in three-species biofilms, indicating that there was multispecies cooperation. Importantly, these community dynamics yielded an 18-fold increase in the F. nucleatum biomass between 4 h and 18 h in the flow cell inoculated with three species. q-PCR analysis of static biofilms revealed that maximum growth of the three species occurred at 24 h to 36 h. Lower numbers of cells were observed at 48 h, suggesting that saliva could not support higher cell densities as the sole nutrient. Integration of F. nucleatum into multispecies commensal communities was evident from the interdigitation of Fusobacteria in coaggregates with A. naeslundii and S. oralis and from the improved growth of Fusobacteria, which was dependent on the presence of A. naeslundii.
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Coaggregation and Distance-Critical Communication
Virulence Mechanisms of Bacterial Pathogens Fourth Edition, 2007Co-Authors: Paul E. Kolenbrander, Nicholas S. Jakubovics, Natalia I. Chalmers, Gilad BachrachAbstract:Interactions between and among bacterial species within a microcommunity occur in an environment that is distinct from the surrounding space. Interactions among species within one community are likely to be distinct from those within a different community. The context of mixed-species communities discussed in this chapter is primarily the human oral cavity, and the chapter focuses on the concept of distance-critical communication and its role in mediating commensalism as well as pathogenesis. The exhibition of extensive coaggregation partnerships by oral plaque bacteria suggests that distance-critical communication typically occurs within the tightly packed microcommunities known to characterize human dental plaque. Coaggregates formed among Methanothermobacter thermautotrophicus, butyrate-oxidizing Syntrophothermus lipocalidus, and acetate-oxidizing Thermacetogenium phaeum, indicating that coaggregations are relevant to interspecies hydrogen transfer among several syntrophic methanogenic consortia. Coaggregation and adhesion to host cells are primary characteristics of all oral Fusobacteria. Fusobacteria coaggregate with all early and late oral colonizers. In place of producing strong toxins and enzymes, Fusobacteria enhance their virulence functions through their ability to interact with other cell types. Many oral streptococci produce IgA1 proteases, which assist the community in evading the principal mediator of adaptive immunity.
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Characterization of the Novel Fusobacterium nucleatum Plasmid pKH9 and Evidence of an Addiction System
Applied and environmental microbiology, 2004Co-Authors: Gilad Bachrach, R Naor, Susan Kinder Haake, Alon Glick, Ronen Hazan, Roxanna N. Andersen, Paul E. KolenbranderAbstract:Fusobacterium nucleatum is an important oral anaerobic pathogen involved in periodontal and systemic infections. Studies of the molecular mechanisms involved in Fusobacterial virulence and adhesion have been limited by lack of systems for efficient genetic manipulation. Plasmids were isolated from eight strains of F. nucleatum. The smallest plasmid, pKH9 (4,975 bp), was characterized and used to create new vectors for Fusobacterial genetic manipulation. DNA sequence analysis of pKH9 revealed an open reading frame (ORF) encoding a putative autonomous rolling circle replication protein (Rep), an ORF predicted to encode a protein homologous to members of the FtsK/SpoIIIE cell division-DNA segregation protein family, and an operon encoding a putative toxin-antitoxin plasmid addiction system (txf-axf). Deletion analysis localized the pKH9 replication region in a 0.96-kbp fragment. The pKH9 rep gene is not present in this fragment, suggesting that pKH9 can replicate in Fusobacteria independently of the Rep protein. A pKH9-based, compact Escherichia coli-F. nucleatum shuttle plasmid was constructed and found to be compatible with a previously described pFN1-based Fusobacterial shuttle plasmid. Deletion of the pKH9 putative addiction system (txf-axf) reduced plasmid stability in Fusobacteria, indicating its addiction properties and suggesting it to be the first plasmid addiction system described for Fusobacteria. pKH9, its genetic elements, and its shuttle plasmid derivatives can serve as useful tools for investigating Fusobacterial properties important in biofilm ecology and pathogenesis.
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Helicobacter pylori adheres selectively to Fusobacterium spp
Oral Microbiology and Immunology, 1998Co-Authors: R. N. Andersen, N Ganeshkumar, Paul E. KolenbranderAbstract:Helicobacter pylori strains ATCC 43504 and ATCC 43629 were tested for their ability to coaggregate with 79 strains of bacteria representing 16 genera. All except two of the strains were of human origin, and most of the strains were isolated from the oral cavity. The helicobacters failed to coaggregate with all strains except the Fusobacteria. Several coaggregations were partially or completely inhibited by lactose. Strong coaggregation was seen with each of four subspecies of Fusobacterium nucleatum and with Fusobacterium periodonticum ATCC 33693, all of human dental plaque origin. In contrast, the helicobacters failed to coaggregate with non-plaque isolates, Fusobacterium mortiferum ATCC 25557 and Fusobacterium ulcerans ATCC 49185. Heat treatment of the Fusobacteria inactivated their ability to coaggregate, whereas heating of the helicobacter partners had no effect, suggesting the presence of an adhesin on the Fusobacteria and a corresponding receptor on the helicobacters. The potential ability of H. pylori to colonize the oral cavity by adhering selectively to the ubiquitous Fusobacteria gives credence to the possibility that dental plaque may serve as a reservoir for this pathogen outside of the stomach.
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Intergeneric coaggregation of oral Treponema spp. with Fusobacterium spp. and intrageneric coaggregation among Fusobacterium spp.
Infection and immunity, 1995Co-Authors: Paul E. Kolenbrander, R. N. Andersen, K D Parrish, E. P. GreenbergAbstract:A total of 22 strains of Treponema spp. including members of all four named human oral species were tested for coaggregation with 7 strains of oral Fusobacteria, 2 strains of nonoral Fusobacteria, and 45 strains of other oral bacteria, which included actinobacilli, actinomyces, capnocytophagae, eubacteria, porphyromonads, prevotellae, selenomonads, streptococci, and veillonellae. None of the treponemes coaggregated with any of the latter 45 oral strains or with the two nonoral Fusobacteria. All treponemes, eight Treponema denticola strains, eight T. socranskii strains, four oral pectinolytic treponemes, one T. pectinovorum strain, and one T. vincentii strain coaggregated with at least one strain of the Fusobacteria tested as partners. The partners consisted of one strain of Fusobacterium periodonticum, five F. nucleatum strains including all four subspecies of F. nucleatum, and a strain of F. simiae obtained from the dental plaque of a monkey. In the more than 100 coaggregations observed, the Fusobacterial partner was heat inactivated (85 degrees C for 30 min), while the treponemes were unaffected by the heat treatment. Furthermore, the Fusobacteria were usually inactivated by proteinase K treatment, and the treponemes were not affected. Only the T. denticola coaggregations were inhibited by lactose and D-galactosamine. None were inhibited by any of 23 other different sugars or L-arginine. Intragenic coaggregations were seen among the subspecies of F. nucleatum and with F. periodonticum, and none were inhibited by any of the sugars tested or by L-arginine. No intrageneric coaggregations were observed among the treponemes. These data indicate that the human oral treponemes show a specificity for oral Fusobacteria as coaggregation partners. Such cell-to cell contact may facilitate efficient metabolic communication and enhance the proliferation of each cell in the progressively more severe stages of periodontal disease.
Beverley Adriaans - One of the best experts on this subject based on the ideXlab platform.
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The infectious aetiology of tropical ulcer—a study of the role of anaerobic bacteria
British Journal of Dermatology, 2006Co-Authors: Beverley Adriaans, B S Drasar, D.c.a. RobinsonAbstract:SUMMARY We have cultured anaerobic bacteria from patients with tropical ulcers. Fusobacteria were isolated most frequently. Anaerobes were always present, together with aerobes or facultative anaerobes, particularly in early phase ulcers, suggesting that the combination of organisms is important in the pathogenesis of the disease. Spirochaetes were identified in material examined by light and electron microscopy, but were not cultured.
