Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins - PubMed (original) (raw)

Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins

Andreas Zanzoni et al. Microbiome. 2017.

Abstract

Background: Fusobacterium nucleatum is a gram-negative anaerobic species residing in the oral cavity and implicated in several inflammatory processes in the human body. Although F. nucleatum abundance is increased in inflammatory bowel disease subjects and is prevalent in colorectal cancer patients, the causal role of the bacterium in gastrointestinal disorders and the mechanistic details of host cell functions subversion are not fully understood.

Results: We devised a computational strategy to identify putative secreted F. nucleatum proteins (FusoSecretome) and to infer their interactions with human proteins based on the presence of host molecular mimicry elements. FusoSecretome proteins share similar features with known bacterial virulence factors thereby highlighting their pathogenic potential. We show that they interact with human proteins that participate in infection-related cellular processes and localize in established cellular districts of the host-pathogen interface. Our network-based analysis identified 31 functional modules in the human interactome preferentially targeted by 138 FusoSecretome proteins, among which we selected 26 as main candidate virulence proteins, representing both putative and known virulence proteins. Finally, six of the preferentially targeted functional modules are implicated in the onset and progression of inflammatory bowel diseases and colorectal cancer.

Conclusions: Overall, our computational analysis identified candidate virulence proteins potentially involved in the F. nucleatum-human cross-talk in the context of gastrointestinal diseases.

Keywords: Bioinformatics; Colorectal cancer; Fusobacterium nucleatum; Inflammatory bowel diseases; Interaction network; Molecular mimicry; Secretome; Short linear motifs; Virulence proteins.

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Conflict of interest statement

This study is based on publicly available datasets only. Thus, no ethical approval is needed/applicable nor is consent from any participants.

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Fig. 1

Flow strategy of our computational approach

Fig. 2

Fig. 2

Disorder propensity of the _Fuso_Secretome**.** SignalP-secreted proteins show a significantly higher fraction of disordered residues compared to non-secreted proteins (P value = 1.9 × 10−4, Kolgomorov–Smirnov test, two-sided)

Fig. 3

Fig. 3

Topological properties of inferred human interactors in the human interactome. a Inferred human interactors have more interaction partners and b higher values of betweenness centrality compared to non-interacting proteins in the human interactome

Fig. 4

Fig. 4

Interaction network between _Fuso_Secretome candidate virulence proteins and preferentially targeted modules. a Candidate virulence proteins are depicted as green rectangular nodes labeled with respective gene symbol, whereas network modules as orange circles, whose size is proportional to the number of proteins belonging to each module and are labeled with the corresponding identifier. Edge width is proportional to the number of inferred interactions of a virulence protein with a given module. Network modules enriched in gut-related disease gene sets are labeled with symbols of different colors (i.e., light blue star: Crohn’s disease, CD; dark blue star: Inflammatory bowel disease, IBD; violet star: genes whose expression correlates with F. nucleatum abundance in colorectal cancer patients, FusoExpr; rose star: genes mutated in colorectal cancer, CRC-mutated; rose zig-zag arrow: dysregulated expression during colorectal cancer progression, CRC-dysregulated). b The protein Fap2 (FN1449) interacts with 9 proteins (nodes with a green border) of Module 9 and c the MORN2 domain containing protein (FN2118) interacts with 8 proteins in Module 89

Fig. 5

Fig. 5

Enrichment of _Fuso_Secretome inferred human interactors and gut disease related proteins in network modules. Each column of the heatmap represents a module. The color of the cells corresponds to the log-transformed enrichment ratio. Pink circles indicate enriched sets. Modules showing a significant dysregulation in CRC progression are highlighted by an empty circle with green border. For the six modules showing an enrichment in inferred interactions and at least in one of gut disease related proteins, the most representative functions are reported. FusoExpr: genes whose expression correlates with F. nucleatum abundance in CRC patients; CRC: genes mutated in colorectal cancer samples; IBD: genes associated to inflammatory bowel disease; CD and UC: genes specifically associated to Crohn’s disease and ulcerative colitis respectively

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