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

Abstract

Background: Bacterial 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.

Results: We 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 Alzheimer's disease.

Conclusions: Present 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.

Fig. 1

Scatter diagram of relative abundance of 7194 orthologs found in 2527 decoded bacterial genomes. The horizontal axis represents the percentage of nonpathogenic strains presenting the ortholog (Anp) whereas the vertical axis represents the corresponding percentage in pathogenic strain subpopulation (Ap). The pathogen-abundant (PA > 4) and nonpathogen-abundant orthologs (PA < 0.25) were marked in red and green, respectively. Note that PA = Ap/Anp

Fig. 2

Histogram showing the frequency of occurrence of orthologs with respect to the pathogen abundance score (PA). The two edges of the histogram (PA > 4, PA < 0.25) are marked in red and green, respectively

Fig. 3

Pie charts indicating the distribution of orthologs of the present study with respect to ortholog abundance (3A) and the virulence factors presented by the VFDB web platform (3B) as a function of the pathogen abundance score PA

Fig. 4

Pie chart for statistical enrichment of KEGG pathways by pathogen-abundant (PA > 4, red) and nonpathogen-abundant (PA < 0.25, blue) orthologs, respectively

Fig. 5

Gene ontology molecular function distributions in pathogen-abundant orthologs (PA > 4, blue) and in VFDB (red), respectively

Fig. 6

Examples of gene circuitry containing pathogen-linked ortholog clusters in KEGG reference pathways. Orthologs with PA > 4 but not present in VFDB were shaded in pink whereas orthologs with PA > 4 and also in VFDB in orange. The numbers indicating specific circuitry correspond to their identification numbers in Table 3

Fig. 7

Examples of gene circuitry in KEGG Reference pathways, which are linked to pathogenicity via within-genus comparison. The orthologs linked to pathogenicity in these circuits are shaded in pink. The numbers indicating specific circuitry correspond to their identification numbers in Additional file 5

Fig. 8

Examples of gene circuitry containing nonpathogen-linked ortholog clusters in KEGG reference pathways. Orthologs with PA < 1/4 are shaded in pink. The numbers indicating specific circuitry correspond to their identification numbers in Table 4