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Transcription Elongation Factor GreA Plays a Key Role in Cellular Invasion and Virulence of Francisella tularensis subsp. novicida.

ABSTRACT: Francisella tularensis is a facultative intracellular Gram-negative bacterium that causes the zoonotic disease tularemia. We identified the transcription elongation factor GreA as a virulence factor in our previous study, but its role was not defined. Here, we investigate the effects of the inactivation of the greA gene, generating a greA mutant of F. tularensis subsp. novicida. Inactivation of greA impaired the bacterial invasion into and growth within host cells, and subsequently virulence in mouse infection model. A transcriptomic analysis (RNA-Seq) showed that the loss of GreA caused the differential expression of 196 bacterial genes, 77 of which were identified as virulence factors in previous studies. To confirm that GreA regulates the expression of virulence factors involved in cell invasion by Francisella, FTN_1186 (pepO) and FTN_1551 (ampD) gene mutants were generated. The ampD deletion mutant showed reduced invasiveness into host cells. These results strongly suggest that GreA plays an important role in the pathogenesis of Francisella by affecting the expression of virulence genes and provide new insights into the complex regulation of Francisella infection.

SUBMITTER: Cui G

PROVIDER: S-EPMC5932009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Francisella tularensis is composed of a number of subspecies with varied geographic distribution, host ranges, and virulence. In view of these marked differences, comparative functional genomics may elucidate some of the molecular mechanism(s) behind these differences. In this study a shared probe microarray was designed that could be used to compare the transcriptomes of Francisella tularensis subsp. tularensis Schu S4 (Ftt), Francisella tularensis subsp. holarctica OR960246 (Fth), Francisella tularensis subsp. holarctica LVS (LVS), and Francisella novicida U112 (Fn). To gain insight into expression differences that may be related to the differences in virulence of these subspecies, transcriptomes were measured from each strain grown in vitro under identical conditions, utilizing a shared probe microarray. The human avirulent Fn strain exhibited high levels of transcription of genes involved in general metabolism, which are pseudogenes in the human virulent Ftt and Fth strains, consistent with the process of genome decay in the virulent strains. Genes encoding an efflux system (emrA2 cluster of genes), siderophore (fsl operon), acid phosphatase, LPS synthesis, polyamine synthesis, and citrulline ureidase were all highly expressed in Ftt when compared to Fn, suggesting that some of these may contribute to the relative high virulence of Ftt. Genes expressed at a higher level in Ftt when compared to the relatively less virulent Fth included genes encoding isochorismatases, cholylglycine hydrolase, polyamine synthesis, citrulline ureidase, Type IV pilus subunit, and the Francisella Pathogenicity Island protein PdpD. Fth and LVS had very few expression differences, consistent with the derivation of LVS from Fth. This study demonstrated that a shared probe microarray designed to detect transcripts in multiple species/subspecies of Francisella enabled comparative transcriptional analyses that may highlight critical differences that underlie the relative pathogenesis of these strains for humans. This strategy could be extended to other closely-related bacterial species for inter-strain and inter-species analyses.

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Transcription Elongation Factor GreA Plays a Key Role in Cellular Invasion and Virulence of Francisella tularensis subsp. novicida.

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