The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Daniel J. Slade - One of the best experts on this subject based on the ideXlab platform.
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Reevaluating the Fusobacterium Virulence Factor Landscape
bioRxiv, 2019Co-Authors: Ariana Umana, Blake E. Sanders, Michael A. Casasanta, Barath Udayasuryan, Scott S. Verbridge, Daniel J. SladeAbstract:Fusobacterium are Gram-negative, anaerobic, opportunistic pathogens involved in multiple diseases, including the oral pathogen Fusobacterium nucleatum being linked to the progression and severity of colorectal cancer. The global identification of virulence factors in Fusobacterium has been greatly hindered by a lack of properly assembled and annotated genomes. Using newly completed genomes from nine strains and seven species of Fusobacterium, we report the identification and correction of virulence factors from the Type 5 secreted autotransporter and FadA protein families, with a focus on the genetically tractable strain F. nucleatum subsp. nucleatum ATCC 23726 and the classic typed strain F. nucleatum subsp. nucleatum ATCC 25586. Within the autotransporters, we employed protein sequence similarity networks to identify subsets of virulence factors, and show a clear differentiation between the prediction of outer membrane adhesins, serine proteases, and proteins with unknown function. These data have defined protein subsets within the Type 5a effectors that are present in predicted invasive strains but are broadly lacking in passively invading strains; a key phenotype associated with Fusobacterium virulence. However, our data shows that prior bioinformatic analysis that predicted species of Fusobacterium to be non-invasive can indeed invade human cells, and that pure phylogenetic analysis to determine the virulence within this bacterial genus should be used cautiously and subsequently paired with experiments to validate these hypotheses. In addition, we provide data that show a complex interplay between autotransporters, MORN2 domain containing proteins, and FadA adhesins that we hypothesize synergistically contribute to host cell interactions and invasion. In summary, we report that accurate open reading frame annotations using complete Fusobacterium genomes, in combination with experimental validation of invasion, redefines the repertoire of virulence factors that could be contributing to the species specific pathology of multiple Fusobacterium induced infections and diseases.
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fusoportal an interactive repository of hybrid minion sequenced Fusobacterium genomes improves gene identification and characterization
mSphere, 2018Co-Authors: Blake E. Sanders, Ariana Umana, Justin A Lemkul, Daniel J. SladeAbstract:ABSTRACT Here we present FusoPortal, an interactive repository of Fusobacterium genomes that were sequenced using a hybrid MinION long-read sequencing pipeline, followed by assembly and annotation using a diverse portfolio of predominantly open-source software. Significant efforts were made to provide genomic and bioinformatic data as downloadable files, including raw sequencing reads, genome maps, gene annotations, protein functional analysis and classifications, and a custom BLAST server for FusoPortal genomes. FusoPortal has been initiated with eight complete genomes, of which seven were previously only drafts that ranged from 24 to 67 contigs. We have showcased that the genomes in FusoPortal provide accurate open reading frame annotations and have corrected a number of large (>3-kb) genes that were previously misannotated due to contig boundaries. In summary, FusoPortal (http://fusoportal.org) is the first database of MinION-sequenced and completely assembled Fusobacterium genomes, and this central Fusobacterium genomic and bioinformatic resource will aid the scientific community in developing a deeper understanding of how this human pathogen contributes to an array of diseases, including periodontitis and colorectal cancer. IMPORTANCE In this report, we describe a hybrid MinION whole-genome sequencing pipeline and the genomic characteristics of the first eight Fusobacterium strains deposited in the FusoPortal database. This collection of highly accurate and complete genomes drastically improves upon previous multicontig assemblies by correcting and newly identifying a significant number of open reading frames. We believe that the availability of this resource will result in the discovery of proteins and molecular mechanisms used by an oral pathogen, with the potential to further our understanding of how Fusobacterium nucleatum contributes to a repertoire of diseases, including periodontitis, preterm birth, and colorectal cancer.
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fusoportal an interactive repository of hybrid minion sequenced Fusobacterium genomes improves gene identification and characterization
bioRxiv, 2018Co-Authors: Blake E. Sanders, Ariana Umana, Justin A Lemkul, Daniel J. SladeAbstract:Here we present FusoPortal, an interactive repository of Fusobacterium genomes that were sequenced using a hybrid MinION long-read sequencing pipeline, followed by assembly and annotation using a diverse portfolio of predominantly open-source software. Significant efforts were made to provide genomic and bioinformatic data as downloadable files, including raw sequencing reads, genome maps, gene annotations, protein functional analysis and classifications, and a custom BLAST server for FusoPortal genomes. FusoPortal has been initiated with eight complete genomes, of which seven were previously only drafts that varied from 24-67 contigs. We showcase that genomes in FusoPortal provide accurate open reading frame annotations, and have corrected a number of large genes (>3 kb) that were previously misannotated due to contig boundaries. In summary, FusoPortal (http://fusoportal.org) is the first database of MinION sequenced and completely assembled Fusobacterium genomes, and this central Fusobacterium genomic and bioinformatic resource will aid the scientific community in developing a deeper understanding of how this human pathogen contributes to an array of diseases including periodontitis and colorectal cancer.
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a chemical and biological toolbox for type vd secretion characterization of the phospholipase a1 autotransporter fpla from Fusobacterium nucleatum
Journal of Biological Chemistry, 2017Co-Authors: Michael A. Casasanta, Kyla Cochrane, Emma Allenvercoe, Hans B Smith, Alison J Duncan, Ann C Varano, Daniel J. SladeAbstract:Abstract Fusobacterium nucleatum is an oral pathogen that is linked to multiple human infections and colorectal cancer. Strikingly, F. nucleatum achieves virulence in the absence of large, multiprotein secretion systems (Types I, II, III, IV, and VI), which are widely used by Gram-negative bacteria for pathogenesis. By contrast, F. nucleatum strains contain genomic expansions of Type V secreted effectors (autotransporters) that are critical for host cell adherence, invasion, and biofilm formation. Here, we present the first characterization of an F. nucleatum Type Vd phospholipase class A1 autotransporter (strain ATCC 25586, gene FN1704) that we hereby rename Fusobacterium phospholipase autotransporter (FplA). Biochemical analysis of multiple Fusobacterium strains revealed that FplA is expressed as a full-length 85-kDa outer membrane–embedded protein or as a truncated phospholipase domain that remains associated with the outer membrane. Whereas the role of Type Vd secretion in bacteria remains unidentified, we show that FplA binds with high affinity to host phosphoinositide-signaling lipids, revealing a potential role for this enzyme in establishing an F. nucleatum intracellular niche. To further analyze the role of FplA, we developed an fplA gene knock-out strain, which will guide future in vivo studies to determine its potential role in F. nucleatum pathogenesis. In summary, using recombinant FplA constructs, we have identified a biochemical toolbox that includes lipid substrates for enzymatic assays, potent inhibitors, and chemical probes to detect, track, and characterize the role of Type Vd secreted phospholipases in Gram-negative bacteria.
O Barraud - One of the best experts on this subject based on the ideXlab platform.
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Fusobacterium nucleatum infections clinical spectrum and bacteriological features of 78 cases
Infection, 2016Co-Authors: E Denes, O BarraudAbstract:Purpose Few series describe the clinical spectrum of Fusobacterium spp. infections. Among them, fewer discuss F. nucleatum, even though there are many clinical cases.
Susan Bullman - One of the best experts on this subject based on the ideXlab platform.
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abstract 5129 Fusobacterium and co occurring microbes in primary and metastatic colorectal cancer
Cancer Research, 2018Co-Authors: Susan Bullman, Chandra Sekhar Pedamallu, Ewa Sicinska, Thomas E Clancy, Shuji Ogino, Josep Tabernero, Charles S Fuchs, William C Hahn, Paolo Nuciforo, Matthew MeyersonAbstract:In colorectal cancer, malignant cells are surrounded by a complex microenvironment encompassing a range of non-transformed cells, but also a diverse collection of microorganisms. A growing body of evidence demonstrates the role of particular microorganisms in modulating inflammatory environments and promoting tumor growth and metastasis. Studies by our group, and others, reveal a consistent enrichment of Fusobacterium nucleatum in human colorectal cancer, and F. nucleatum has been shown to accelerate tumorigenesis using both in vitro and in vivo preclinical models. We recently demonstrated via microbiome analysis and microbial culture that fusobacteria and its co-occurring microbiota, including Bacteroides, Prevotella and Selenomonas species, persist in liver metastasis of Fusobacterium-positive colorectal cancers. Many of the liver metastasis share the same dominant microbiome (>1% relative abundance) as the paired primary colorectal tumor. Additionally, we have cultured fusobacteria from paired primary and metastatic tumors, and following whole genome sequencing analysis reveal the same strains of Fusobacterium are present in the primary tumors and distant site metastasis, despite the tissue being resected months or even years apart. In situ hybridization analysis demonstrate that Fusobacterium is invasive in the primary tumors and distal metastasis, and is associated with cells whose morphology is consistent with malignant cells. Additionally, we demonstrate via microbiome analysis and microbial culture, that Fusobacterium and its co-occurring microbiome also persist and remain viable in patient derived xenografts of colorectal cancers. Treatment of a patent derived colon cancer xenograft harboring F. nucleatum, with an antibiotic that kills F. nucleatum reduced tumor growth, cancer cell proliferation and tumor fusobacterial load. We have isolated and sequenced the genomes of over 60 F. nucleatum strains from human colorectal cancer tumors with detailed microbiome and patient metadata. In addition to phenotypic analysis and small molecule inhibitory screens of the F. nucleatum colorectal cancer isolates, we are conducting comparative genomic analysis with F. nucleatum isolates from the oral cavity of non-cancer patients to determine colorectal cancer-specific markers and identify targetable genomic attributes. In summary, these findings suggest that the tumor microbiota are intrinsic and essential components of the cancer microenvironment and warrant further investigation into the modulation of the tumor microbiota for the treatment of Fusobacterium-associated colorectal cancer in both early and late stage disease. Citation Format: Susan Bullman, Chandra S. Pedamallu, Ewa Sicinska, Thomas Clancy, Shuji Ogino, Josep Tabernero, Charles Fuchs, William C. Hahn, Paolo Nuciforo, Matthew Meyerson. Fusobacterium and co-occurring microbes in primary and metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5129.
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analysis of Fusobacterium persistence and antibiotic response in colorectal cancer
Science, 2017Co-Authors: Susan Bullman, Chandra Sekhar Pedamallu, Ewa Sicinska, Thomas E Clancy, Xiaoyang Zhang, Donna Neuberg, Katherine H HuangAbstract:Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides , Selenomonas , and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that Fusobacterium is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable Fusobacterium and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced Fusobacterium load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium -associated colorectal cancer.
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whole exome sequencing analyses of colorectal cancer with Fusobacterium nucleatum
The FASEB Journal, 2017Co-Authors: Reiko Nishihara, Susan Bullman, Aleksandar D Kostic, Andrew T Chan, Jasmine Mu, Marios Giannakis, Kosume Mima, Zhi Rong Qian, Curtis Huttenhower, Wendy S GarrettAbstract:IntroductionGut microbiota plays an important role in intestinal cancer pathogenesis. An accumulating body of evidence demonstrates the association between Fusobacterium nucleatum (F. nucleatum) an...
Thomas E Clancy - One of the best experts on this subject based on the ideXlab platform.
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abstract 5129 Fusobacterium and co occurring microbes in primary and metastatic colorectal cancer
Cancer Research, 2018Co-Authors: Susan Bullman, Chandra Sekhar Pedamallu, Ewa Sicinska, Thomas E Clancy, Shuji Ogino, Josep Tabernero, Charles S Fuchs, William C Hahn, Paolo Nuciforo, Matthew MeyersonAbstract:In colorectal cancer, malignant cells are surrounded by a complex microenvironment encompassing a range of non-transformed cells, but also a diverse collection of microorganisms. A growing body of evidence demonstrates the role of particular microorganisms in modulating inflammatory environments and promoting tumor growth and metastasis. Studies by our group, and others, reveal a consistent enrichment of Fusobacterium nucleatum in human colorectal cancer, and F. nucleatum has been shown to accelerate tumorigenesis using both in vitro and in vivo preclinical models. We recently demonstrated via microbiome analysis and microbial culture that fusobacteria and its co-occurring microbiota, including Bacteroides, Prevotella and Selenomonas species, persist in liver metastasis of Fusobacterium-positive colorectal cancers. Many of the liver metastasis share the same dominant microbiome (>1% relative abundance) as the paired primary colorectal tumor. Additionally, we have cultured fusobacteria from paired primary and metastatic tumors, and following whole genome sequencing analysis reveal the same strains of Fusobacterium are present in the primary tumors and distant site metastasis, despite the tissue being resected months or even years apart. In situ hybridization analysis demonstrate that Fusobacterium is invasive in the primary tumors and distal metastasis, and is associated with cells whose morphology is consistent with malignant cells. Additionally, we demonstrate via microbiome analysis and microbial culture, that Fusobacterium and its co-occurring microbiome also persist and remain viable in patient derived xenografts of colorectal cancers. Treatment of a patent derived colon cancer xenograft harboring F. nucleatum, with an antibiotic that kills F. nucleatum reduced tumor growth, cancer cell proliferation and tumor fusobacterial load. We have isolated and sequenced the genomes of over 60 F. nucleatum strains from human colorectal cancer tumors with detailed microbiome and patient metadata. In addition to phenotypic analysis and small molecule inhibitory screens of the F. nucleatum colorectal cancer isolates, we are conducting comparative genomic analysis with F. nucleatum isolates from the oral cavity of non-cancer patients to determine colorectal cancer-specific markers and identify targetable genomic attributes. In summary, these findings suggest that the tumor microbiota are intrinsic and essential components of the cancer microenvironment and warrant further investigation into the modulation of the tumor microbiota for the treatment of Fusobacterium-associated colorectal cancer in both early and late stage disease. Citation Format: Susan Bullman, Chandra S. Pedamallu, Ewa Sicinska, Thomas Clancy, Shuji Ogino, Josep Tabernero, Charles Fuchs, William C. Hahn, Paolo Nuciforo, Matthew Meyerson. Fusobacterium and co-occurring microbes in primary and metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5129.
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analysis of Fusobacterium persistence and antibiotic response in colorectal cancer
Science, 2017Co-Authors: Susan Bullman, Chandra Sekhar Pedamallu, Ewa Sicinska, Thomas E Clancy, Xiaoyang Zhang, Donna Neuberg, Katherine H HuangAbstract:Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides , Selenomonas , and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that Fusobacterium is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable Fusobacterium and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced Fusobacterium load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium -associated colorectal cancer.
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Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor immune microenvironment
Cell Host & Microbe, 2013Co-Authors: Thomas E Clancy, Aleksandar D Kostic, Eunyoung Chun, Lauren Robertson, Jonathan N Glickman, Carey Ann Gallini, Monia Michaud, Daniel C ChungAbstract:Summary Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc Min/+ mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc Min/+ mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression.
Aleksandar D Kostic - One of the best experts on this subject based on the ideXlab platform.
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whole exome sequencing analyses of colorectal cancer with Fusobacterium nucleatum
The FASEB Journal, 2017Co-Authors: Reiko Nishihara, Susan Bullman, Aleksandar D Kostic, Andrew T Chan, Jasmine Mu, Marios Giannakis, Kosume Mima, Zhi Rong Qian, Curtis Huttenhower, Wendy S GarrettAbstract:IntroductionGut microbiota plays an important role in intestinal cancer pathogenesis. An accumulating body of evidence demonstrates the association between Fusobacterium nucleatum (F. nucleatum) an...
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Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor immune microenvironment
Cell Host & Microbe, 2013Co-Authors: Thomas E Clancy, Aleksandar D Kostic, Eunyoung Chun, Lauren Robertson, Jonathan N Glickman, Carey Ann Gallini, Monia Michaud, Daniel C ChungAbstract:Summary Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc Min/+ mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc Min/+ mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression.
