Encyclopedia of bacterial gene circuits whose presence or absence correlate with pathogenicity – a large-scale system analysis of decoded bacterial genomes

Abstract

BackgroundBacterial infections comprise a global health challenge as the incidences of antibiotic resistance increase. Pathogenic potential of bacteria has been shown to be context dependent, varying in response to environment and even within the strains of the same genus.ResultsWe used the KEGG repository and extensive literature searches to identify among the 2527 bacterial genomes in the literature those implicated as pathogenic to the host, including those which show pathogenicity in a context dependent manner. Using data on the gene contents of these genomes, we identified sets of genes highly abundant in pathogenic but relatively absent in commensal strains and vice versa. In addition, we carried out genome comparison within a genus for the seventeen largest genera in our genome collection. We projected the resultant lists of ortholog genes onto KEGG bacterial pathways to identify clusters and circuits, which can be linked to either pathogenicity or synergy. Gene circuits relatively abundant in nonpathogenic bacteria often mediated biosynthesis of antibiotics. Other synergy-linked circuits reduced drug-induced toxicity. Pathogen-abundant gene circuits included modules in one-carbon folate, two-component system, type-3 secretion system, and peptidoglycan biosynthesis. Antibiotics-resistant bacterial strains possessed genes modulating phagocytosis, vesicle trafficking, cytoskeletal reorganization, and regulation of the inflammatory response. Our study also identified bacterial genera containing a circuit, elements of which were previously linked to Alzheimers disease.ConclusionsPresent study produces for the first time, a signature, in the form of a robust list of gene circuitry whose presence or absence could potentially define the pathogenicity of a microbiome. Extensive literature search substantiated a bulk majority of the commensal and pathogenic circuitry in our predicted list. Scanning microbiome libraries for these circuitry motifs will provide further insights into the complex and context dependent pathogenicity of bacteria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1957-7) contains supplementary material, which is available to authorized users.

Small Molecules That Sabotage Bacterial Virulence

“…TCS represent a family of targets that are of particular interest to develop antivirulence therapies as they are not found in mammalian cells, limiting potential off target effects against host-associated factors [29]. Further, deletion of TCS have been shown to significantly attenuate pathogenesis, though many TCS are dispensable for in vitro growth, suggesting that screening for inhibitors of TCS in vitro requires a method alternative to growth inhibition, such as using a reporter system coupled to a gene regulated by the TCS [30, 31]. Inhibiting virulence-associated TCS “blinds” the pathogen from sensing and coordinating an adaptive response to host cues, potentially sensitizing it to antibiotic treatment and immune clearance.…”

Virulence factor activity relationships (VFARs): a bioinformatics perspective

“…34 Bacterial genomes of 949 pathogenic and 1578 non-pathogenic bacteria from more than 26 genera were used to establish the signature bacterial gene circuits. Gene circuits for pathogens were mostly linked with direct pathogenic mechanisms or signaling pathogenic interactions while most gene circuits for non-pathogens were associated with metabolic pathways.…”

Recent “omics” advances in Helicobacter pylori

“…Attempts are being made to use systematic approaches for virulence factor discovery. A study based on 2527 isolates from diverse bacterial genera including 63 H. pylori isolates inferred generalized pathways for pathogenicity in bacteria, therefore identifying genes that could be a target for further studies of H. pylori virulence . Genomewide association studies (GWAS) have recently been applied to Campylobacter a related genus within the Epsilonproteobacteria .…”

“…A study based on 2527 isolates from diverse bacterial genera including 63 H. pylori isolates inferred generalized pathways for pathogenicity in bacteria, therefore identifying genes that could be a target for further studies of H. pylori virulence. 19 Genomewide association studies (GWAS) have recently been applied to Campylobacter a related genus within the Epsilonproteobacteria. 20 In this method, homologous and non-homologous sequence variation is related to specific phenotypes by identifying DNA sequence that is overrepresented in one phenotype group compared to another.…”