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Immunological blocking of spermidine-mediated host-pathogen communication provides effective control against Pseudomonas aeruginosa infection.

ABSTRACT: Pseudomonas aeruginosa is known to cause life-threatening infections. The previous studies showed that the type III secretion system (T3SS) of this pathogen is a key virulence determinant, which is activated by polyamines signals spermidine (Spd) and spermine (Spm) from mammalian host. To test the potential of blocking host-pathogen communication in disease control, in this study we developed a high potency mouse monoclonal antibody (Mab 4E4, IgG1 sub-isotype) by using Spm-protein conjugate as an immunogen. Antibody specificity analysis showed that the antibody specifically recognize Spd and Spm. In vitro study showed the antibody significantly protected A549 cells against P. aeruginosa infection, and this protection was achieved by blocking polyamine uptake and downregulating T3SS expression. In vivo single injection of mouse with Mab 4E4 drastically reduced the serum polyamine level, which was maintained for more than 1 week. In a murine model of P. aeruginosa acute infection, injection of Mab 4E4 protected mice from lung injury and significantly improved the survival rate of mice.

SUBMITTER: Wang J

PROVIDER: S-EPMC6922524 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Immunological blocking of spermidine-mediated host-pathogen communication provides effective control against Pseudomonas aeruginosa infection.

Wang Jianhe J Wang Jing J Zhang Lian-Hui LH

Microbial biotechnology 20180514 1

Pseudomonas aeruginosa is known to cause life-threatening infections. The previous studies showed that the type III secretion system (T3SS) of this pathogen is a key virulence determinant, which is activated by polyamines signals spermidine (Spd) and spermine (Spm) from mammalian host. To test the potential of blocking host-pathogen communication in disease control, in this study we developed a high potency mouse monoclonal antibody (Mab 4E4, IgG1 sub-isotype) by using Spm-protein conjugate as a ...[more]

PMID: 29761642

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Project description:Microorganisms exist in a diverse ecosystem and have evolved many different mechanisms for sensing and influencing the polymicrobial environment around them, utilizing both diffusible and contact-dependent signals. Contact-dependent growth inhibition (CDI) is one such communication system employed by Gram-negative bacteria. In addition to CDI mediation of growth inhibition, recent studies have demonstrated CDI-mediated control of communal behaviors such as biofilm formation. We postulated that CDI may therefore play an active role in host-pathogen interactions, allowing invading strains to establish themselves at polymicrobial mucosal interfaces through competitive interactions while simultaneously facilitating pathogenic capabilities via CDI-mediated signaling. Here, we show that Pseudomonas aeruginosa produces two CDI systems capable of mediating competition under conditions of growth on a surface or in liquid. Furthermore, we demonstrated a novel role for these systems in contributing to virulence in acute infection models, likely via posttranscriptional regulation of beneficial behaviors. While we did not observe any role for the P. aeruginosa CDI systems in biofilm biogenesis, we did identify for the first time robust CDI-mediated competition during interaction with a mammalian host using a model of chronic respiratory tract infection, as well as evidence that CDI expression is maintained in chronic lung infections. These findings reveal a previously unappreciated role for CDI in host-pathogen interactions and emphasize their importance during infection. IMPORTANCE How bacteria compete and communicate with each other is an increasingly recognized aspect of microbial pathogenesis with a major impact on disease outcomes. Gram-negative bacteria have recently been shown to employ a contact-dependent toxin-antitoxin system to achieve both competition and regulation of their physiology. Here, we show that this system is vital for virulence in acute infection as well as for establishment of chronic infection in the multidrug-resistant pathogen Pseudomonas aeruginosa. Greater understanding of the mechanisms underlying bacterial virulence and infection is important for the development of effective therapeutics in the era of increasing antimicrobial resistance.

Project description: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.

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Immunological blocking of spermidine-mediated host-pathogen communication provides effective control against Pseudomonas aeruginosa infection.

Publications

Immunological blocking of spermidine-mediated host-pathogen communication provides effective control against Pseudomonas aeruginosa infection.

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