Target identification in Fusobacterium nucleatum by subtractive genomics approach and enrichment analysis of host-pathogen protein-protein interactions. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Kumar, Amit; Thotakura, Pragna; Tiwary, Basant; Krishna, Ramadas
• Is Part Of: BMC microbiology. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: Fusobacterium nucleatum -- Colorectal cancer -- Subtractive genomics approach -- Therapeutic target proteins -- Host-pathogen protein-protein interactions -- Enrichment analysis -- Functional annotation -- DAVID -- Gene ontology -- Pathway and disease enrichment; Microbiology -- Periodicals; 579.05
• DOI: 10.1186/s12866-016-0700-0
• Languages: English
• ISSNs: 1471-2180

Abstract

Abstract Background Fusobacterium nucleatum, a well studied bacterium in periodontal diseases, appendicitis, gingivitis, osteomyelitis and pregnancy complications has recently gained attention due to its association with colorectal cancer (CRC) progression. Treatment with berberine was shown to reverseF. nucleatum -induced CRC progression in mice by balancing the growth of opportunistic pathogens in tumor microenvironment. Intestinal microbiota imbalance and the infections caused byF. nucleatum might be regulated by therapeutic intervention. Hence, we aimed to predict drug target proteins inF. nucleatum, through subtractive genomics approach and host-pathogen protein-protein interactions (HP-PPIs). We also carried out enrichment analysis of host interacting partners to hypothesize the possible mechanisms involved in CRC progression due toF. nucleatum . Results In subtractive genomics approach, the essential, virulence and resistance related proteins were retrieved from RefSeq proteome ofF. nucleatum by searching against Database of Essential Genes (DEG), Virulence Factor Database (VFDB) and Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT) tool respectively. A subsequent hierarchical screening to identify non-human homologous, metabolic pathway-independent/pathway-specific and druggable proteins resulted in eight pathway-independent and 27 pathway-specific druggable targets. Co-aggregation ofF. nucleatum with host induces proinflammatory gene expression thereby potentiates tumorigenesis. Hence, proteins from IBDsite, a database for inflammatory bowel disease (IBD) research and those involved in colorectal adenocarcinoma as interpreted from The Cancer Genome Atlas (TCGA) were retrieved to predict drug targets based on HP-PPIs withF. nucleatum proteome. Prediction of HP-PPIs exhibited 186 interactions contributed by 103 host and 76 bacterial proteins. Bacterial interacting partners were accounted as putative targets. And enrichment analysis of host interacting partners showed statistically enriched terms that were in positive correlation with CRC, atherosclerosis, cardiovascular, osteoporosis, Alzheimer's and other diseases. Conclusion Subtractive genomics analysis provided a set of target proteins suggested to be indispensable for survival and pathogenicity ofF. nucleatum . These target proteins might be considered for designing potent inhibitors to abrogateF. nucleatum infections. From enrichment analysis, it was hypothesized thatF. nucleatum infection might enhance CRC progression by simultaneously regulating multiple signaling cascades which could lead to up-regulation of proinflammatory responses, oncogenes, modulation of host immune defense mechanism and suppression of DNA repair system.