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Spermidine Is an Intercellular Signal Modulating T3SS Expression in Pseudomonas aeruginosa.

ABSTRACT: Pseudomonas aeruginosa is a vital opportunistic human bacterial pathogen that causes acute and chronic infections. In this study, we set to determine whether the endogenous spermidine biosynthesis plays a role in regulation of type III secretion system (T3SS). The results showed that deletion of speA and speC, which encode putrescine biosynthesis, did not seem to affect cellular spermidine level and the T3SS gene expression. In contrast, mutation of speD and speE encoding spermidine biosynthesis led to significantly decreased spermidine production and expression of T3SS genes. We also showed that endogenous spermidine could auto-induce the transcriptional expression of speE and its full functionality required the transporter SpuDEFGH. Cytotoxicity analysis showed that mutants ΔspeE and ΔspuE were substantially attenuated in virulence compared with their wild-type strain PAO1. Our data imply a possibility that spermidine biosynthesis in P. aeruginosa may not use putrescine as a substrate, and that spermidine signaling pathway may interact with other two T3SS regulatory mechanisms in certain degree, i.e., cAMP-Vfr and GacS/GacA signaling systems. Taken together, these results specify the role of endogenous spermidine in regulation of T3SS in P. aeruginosa and provide useful clues for design and development antimicrobial therapies. IMPORTANCE Type III secretion system (T3SS) is one of the pivotal virulence factors of Pseudomonas aeruginosa responsible for evading phagocytosis, and secreting and translocating effectors into host cells. Previous studies underline the complicated and elaborate regulatory mechanisms of T3SS for the accurate, fast, and malicious pathogenicity of P. aeruginosa. Among these regulatory mechanisms, our previous study indicated that the spermidine from the host was vital to the host-pathogen interaction. However, the role of endogenous spermidine synthesized by P. aeruginosa on the regulation of T3SS expression is largely unknown. Here we reveal the role and regulatory network of endogenous spermidine synthesis in regulation of T3SS and bacterial virulence, showing that the spermidine is an important interspecies signal for modulating the virulence of P. aeruginosa through regulating T3SS expression.

SUBMITTER: Lin Q

PROVIDER: S-EPMC9241758 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The opportunistic pathogen Pseudomonas aeruginosa is a significant cause of infection in immunocompromised individuals, cystic fibrosis patients, and burn victims. To benefit its survival, the bacterium adapt to either a motile or sessile lifestyle when infecting the host. The motile bacterium has an often activated type III secretion system (T3SS), which is virulent to the host, whereas the sessile bacterium harbors an active T6SS and lives in biofilms. Regulatory pathways involving Gac-Rsm or secondary messengers such as c-di-GMP determine which lifestyle is favorable for P. aeruginosa. Here, we introduce the RNA binding protein RtcB as a modulator of the switch between motile and sessile bacterial lifestyles. Using the wild-type P. aeruginosa PAO1, and a retS mutant PAO1(∆retS) in which T3SS is repressed and T6SS active, we show that deleting rtcB led to simultaneous expression of T3SS and T6SS in both PAO1(∆rtcB) and PAO1(∆rtcB∆retS). The deletion of rtcB also increased biofilm formation in PAO1(∆rtcB) and restored the motility of PAO1(∆rtcB∆retS). RNA-sequencing data suggested RtcB as a global modulator affecting multiple virulence factors, including bacterial secretion systems. Competitive killing and infection assays showed that the three T6SS systems (H1, H2, and H3) in PAO1(∆rtcB) were activated into a functional syringe, and could compete with Escherichia coli and effectively infect lettuce. Western blotting and RT-PCR results showed that RtcB probably exerted its function through RsmA in PAO1(∆rtcB∆retS). Quantification of c-di-GMP showed an elevated intracellular levels in PAO1(∆rtcB), which likely drove the switch between T6SS and T3SS, and contributed to the altered phenotypes and characteristics observed. Our data demonstrate a pivotal role of RtcB in the virulence of P. aeruginosa by controlling multiple virulence determinants, such as biofilm formation, motility, pyocyanin production, T3SS, and T6SS secretion systems towards eukaryotic and prokaryotic cells. These findings suggest RtcB as a potential target for controlling P. aeruginosa colonization, establishment, and pathogenicity.

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Spermidine Is an Intercellular Signal Modulating T3SS Expression in Pseudomonas aeruginosa.

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