Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins

Zanzoni, Andreas; Spinelli, Lionel; Braham, Shérazade; Brun, Catherine

doi:10.1186/s40168-017-0307-1

Cited by 28 publications

(20 citation statements)

References 108 publications

(136 reference statements)

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“…MORN2 domain-containing proteins could enhance adhesive and active invasive traits since their genes clustered near those for FadA, RadD, and additional T5aSS autotransporter adhesins. Since this study, a role for these proteins in interspecies interactions has been suggested (15), as they are predicted surface-associated proteins, and some of them are part of the "FusoSecretome" (84). More recently, MORN2 domain-containing proteins were found to be secreted into F. nucleatum outer membrane vesicles (52).…”

Section: Discussionmentioning

confidence: 91%

Utilizing Whole Fusobacterium Genomes To Identify, Correct, and Characterize Potential Virulence Protein Families

et al. 2019

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Fusobacterium spp. are Gram-negative, anaerobic, opportunistic pathogens involved in multiple diseases, including a link between the oral pathogen Fusobacterium nucleatum and the progression and severity of colorectal cancer. The identification and characterization of virulence factors in the genus 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 corrected annotation of verified and potential virulence factors from the type 5 secreted autotransporter, FadA, and MORN2 protein families, with a focus on the genetically tractable strain F. nucleatum subsp. nucleatum ATCC 23726 and type strain F. nucleatum subsp. nucleatum ATCC 25586. Within the autotransporters, we used sequence similarity networks to identify protein subsets and show a clear differentiation between the prediction of outer membrane adhesins, serine proteases, and proteins with unknown function. These data have identified unique subsets of type 5a autotransporters, which are key proteins associated with virulence in F. nucleatum. However, we coupled our bioinformatic data with bacterial binding assays to show that a predicted weakly invasive strain of F. necrophorum that lacks a Fap2 autotransporter adhesin strongly binds human colonocytes. These analyses confirm a gap in our understanding of how autotransporters, MORN2 domain proteins, and FadA adhesins contribute to host interactions and invasion. In summary, we identify candidate virulence genes in Fusobacterium, and caution that experimental validation of host-microbe interactions should complement bioinformatic predictions to increase our understanding of virulence protein contributions in Fusobacterium infections and disease. IMPORTANCE Fusobacterium spp. are emerging pathogens that contribute to mammalian and human diseases, including colorectal cancer. Despite a validated connection with disease, few proteins have been characterized that define a direct molecular mechanism for Fusobacterium pathogenesis. We report a comprehensive examination of virulence-associated protein families in multiple Fusobacterium species and show that complete genomes facilitate the correction and identification of multiple, large type 5a secreted autotransporter genes in previously misannotated or fragmented genomes. In addition, we use protein sequence similarity networks and human cell interaction experiments to show that previously predicted noninvasive strains can indeed bind to and potentially invade human cells and that this could be due to the expansion of specific virulence proteins that drive Fusobacterium infections and disease.

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Section: Discussionmentioning

confidence: 91%

Utilizing Whole Fusobacterium Genomes To Identify, Correct, and Characterize Potential Virulence Protein Families

et al. 2019

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“…For example, NetCooperate [31] uses metabolic network modelling to infer the nutritional interdependencies and co-feeding potential between any two microbial species or between microbial and host species. Zanzoni et al [74] harnessed the power of microbe-host protein-protein interactions to infer the perturbations induced on the host by the pathogen Fusobacterium nucleatum. However, researchers aiming to study the functional effects of microbiome-host interactions face technological and methodological boundaries.…”

Section: Discussionmentioning

confidence: 99%

MicrobioLink: An Integrated Computational Pipeline to Infer Functional Effects of Microbiome–Host Interactions

Andrighetti

Bohár

Lemke

et al. 2020

Cells

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Microbiome–host interactions play significant roles in health and in various diseases including autoimmune disorders. Uncovering these inter-kingdom cross-talks propels our understanding of disease pathogenesis and provides useful leads on potential therapeutic targets. Despite the biological significance of microbe–host interactions, there is a big gap in understanding the downstream effects of these interactions on host processes. Computational methods are expected to fill this gap by generating, integrating, and prioritizing predictions—as experimental detection remains challenging due to feasibility issues. Here, we present MicrobioLink, a computational pipeline to integrate predicted interactions between microbial and host proteins together with host molecular networks. Using the concept of network diffusion, MicrobioLink can analyse how microbial proteins in a certain context are influencing cellular processes by modulating gene or protein expression. We demonstrated the applicability of the pipeline using a case study. We used gut metaproteomic data from Crohn’s disease patients and healthy controls to uncover the mechanisms by which the microbial proteins can modulate host genes which belong to biological processes implicated in disease pathogenesis. MicrobioLink, which is agnostic of the microbial protein sources (bacterial, viral, etc.), is freely available on GitHub.

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“…MORN2 domain-containing proteins could enhance adhesive and active invasive traits as these genes clustered near, FadA, RadD, and additional T5aSS autotransporter adhesins. Since this study, a role for these proteins in interspecies interactions has been suggested (15) , as they are predicted surface-associated proteins and some of them are part of the 'FusoSecretome' (58) . More recently, MORN2 domain containing proteins were found secreted into F. nucleatum outer membrane vesicles (59) .…”

Section: Fusobacterium Open Reading Frame Predictions and Comparison mentioning

confidence: 95%

Reevaluating the Fusobacterium Virulence Factor Landscape

Umaña

Sanders

Yoo

et al. 2019

Preprint

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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.IMPORTANCE Fusobacterium are emerging pathogens that contribute to the progression and severity of multiple mammalian and human infectious diseases, including colorectal cancer. Despite a validated connection with disease, a limited number of proteins have been characterized that define a direct molecular mechanism for pathogenesis in a diverse range of host tissue infections. We report a comprehensive examination of virulence associated protein families in multiple Fusobacterium species, and show that complete genomes facilitate the correction and identification of multiple, large Type 5a secreted autotransporter genes in previously misannotated or fragmented genomes. In addition, we use protein sequence similarity networks and human cell invasion experiments to show that previously predicted non-invasive strains can indeed enter human cells, and that this is likely due to the expansion of specific virulence proteins that drive F. nucleat...

show abstract

Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins

Cited by 28 publications

References 108 publications

Utilizing Whole Fusobacterium Genomes To Identify, Correct, and Characterize Potential Virulence Protein Families

Utilizing Whole Fusobacterium Genomes To Identify, Correct, and Characterize Potential Virulence Protein Families

MicrobioLink: An Integrated Computational Pipeline to Infer Functional Effects of Microbiome–Host Interactions

Reevaluating the Fusobacterium Virulence Factor Landscape

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