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A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant.

ABSTRACT: Emerging evidence suggests the Pseudomonas aeruginosa accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. Here, we utilized a mouse bacteremia model to quantify the virulence of 100 individual P. aeruginosa bloodstream isolates and performed whole-genome sequencing to identify accessory genomic elements correlated with increased bacterial virulence. From this work, we identified a specific contact-dependent growth inhibition (CDI) system enriched among highly virulent P. aeruginosa isolates. CDI systems contain a large exoprotein (CdiA) with a C-terminal toxin (CT) domain that can vary between different isolates within a species. Prior work has revealed that delivery of a CdiA-CT domain upon direct cell-to-cell contact can inhibit replication of a susceptible target bacterium. Aside from mediating interbacterial competition, we observed our virulence-associated CdiA-CT domain to promote toxicity against mammalian cells in culture and lethality during mouse bacteremia. Structural and functional studies revealed this CdiA-CT domain to have in vitro tRNase activity, and mutations that abrogated this tRNAse activity in vitro also attenuated virulence. Furthermore, CdiA contributed to virulence in mice even in the absence of contact-dependent signaling. Overall, our findings indicate that this P. aeruginosa CDI system functions as both an interbacterial inhibition system and a bacterial virulence factor against a mammalian host. These findings provide an impetus for continued studies into the complex role of CDI systems in P. aeruginosa pathogenesis.

SUBMITTER: Allen JP

PROVIDER: S-EPMC7104216 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant.

Allen Jonathan P JP Ozer Egon A EA Minasov George G Shuvalova Ludmilla L Kiryukhina Olga O Satchell Karla J F KJF Hauser Alan R AR

Proceedings of the National Academy of Sciences of the United States of America 20200310 12

Emerging evidence suggests the <i>Pseudomonas aeruginosa</i> accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. Here, we utilized a mouse bacteremia model to quantify the virulence of 100 individual <i>P. aeruginosa</i> bloodstream isolates and performed whole-genome sequencing to identify accessory genomic elements correlated with increased bacterial v ...[more]

PMID: 32156726

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Project description:Strains of the Ralstonia solanacearum species complex in the phylotype IIB group are capable of causing Bacterial Wilt disease in potato and tomato at temperatures lower than 24°C. The capability of these strains to survive and to incite infection at temperatures colder than their normally tropical boundaries represents a threat to United States agriculture in temperate regions. In this work, we used a comparative genomics approach to identify orthologous genes linked to the lower temperature virulence phenotype. Six R. solanacearum cool virulent (CV) strains were compared to six strains non-pathogenic at low temperature (NPLT). CV strains can cause Bacterial Wilt symptoms at temperatures below 24°C, while NPLT cannot. Four R. solanacearum strains were sequenced for this work in order to complete the comparison. An orthologous genes comparison identified 44 genes present only in CV strains and 19 genes present only in NPLT strains. Gene annotation revealed a high percentage of genes compared with whole genomes in the transcriptional regulator and transport categories. A single nucleotide polymorphism (SNP) analysis identified 265 genes containing conserved non-synonymous SNPs in CV strains. Ten genes in the pathogenicity category were identified in this group. Comparisons of type 3 secretion system, type 6 secretion system (T6SS) clusters, and associated effectors did not indicate a correlation with the CV phenotype except for one T6SS VGR effector potentially associated with the CV phenotype. This is the first R. solanacearum genomic comparative analysis of multiple strains with different temperature related virulence. The candidate genes identified by this comparison are potential factors involved in virulence at low temperatures that need to be investigated. The high percentage of transcriptional regulators among the genes present only in CV strains supports the hypothesis that temperature dependent regulation of virulence genes explains the differential virulence phenotype at low temperatures. This comparison contributes to find new possible connections of temperature dependent virulence to the previously described complex regulatory system involving quorum-sensing, phenotype conversion (phcA), acyl-HSL production and responses to SA. It also added novel candidate T6SS effectors and useful detailed information about the T6SS in R. solanacearum.

Project description:BACKGROUND:Recently, a new strain of Cercospora sojina (Race15) has been identified, which has caused the breakdown of resistance in most soybean cultivars in China. Despite this serious yield reduction, little is known about why this strain is more virulent than others. Therefore, we sequenced the Race15 genome and compared it to the Race1 genome sequence, as its virulence is significantly lower. We then re-sequenced 30 isolates of C. sojina from different regions to identifying differential virulence genes using genome-wide association analysis (GWAS). RESULTS:The 40.12-Mb Race15 genome encodes 12,607 predicated genes and contains large numbers of gene clusters that have annotations in 11 different common databases. Comparative genomics revealed that although these two genomes had a large number of homologous genes, their genome structures have evolved to introduce 245 specific genes. The most important 5 candidate virulence genes were located on Contig 3 and Contig 1 and were mainly related to the regulation of metabolic mechanisms and the biosynthesis of bioactive metabolites, thereby putatively affecting fungi self-toxicity and reducing host resistance. Our study provides insight into the genomic basis of C. sojina pathogenicity and its infection mechanism, enabling future studies of this disease. CONCLUSIONS:Via GWAS, we identified five candidate genes using three different methods, and these candidate genes are speculated to be related to metabolic mechanisms and the biosynthesis of bioactive metabolites. Meanwhile, Race15 specific genes may be linked with high virulence. The genes highly prevalent in virulent isolates should also be proposed as candidates, even though they were not found in our SNP analysis. Future work should focus on using a larger sample size to confirm and refine candidate gene identifications and should study the functional roles of these candidates, in order to investigate their potential roles in C. sojina pathogenicity.

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A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant.

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A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant.

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