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Animal Models of Type III Secretion System-Mediated Pathogenesis.

ABSTRACT: The type III secretion system (T3SS) is a conserved virulence factor used by many Gram-negative pathogenic bacteria and has become an important target for anti-virulence drugs. Most T3SS inhibitors to date have been discovered using in vitro screening assays. Pharmacokinetics and other important characteristics of pharmaceuticals cannot be determined with in vitro assays alone. In vivo assays are required to study pathogens in their natural environment and are an important step in the development of new drugs and vaccines. Animal models are also required to understand whether T3SS inhibition will enable the host to clear the infection. This review covers selected animal models (mouse, rat, guinea pig, rabbit, cat, dog, pig, cattle, primates, chicken, zebrafish, nematode, wax moth, flea, fly, and amoeba), where T3SS activity and infectivity have been studied in relation to specific pathogens (Escherichia coli, Salmonella spp., Pseudomonas spp., Shigella spp., Bordetella spp., Vibrio spp., Chlamydia spp., and Yersinia spp.). These assays may be appropriate for those researching T3SS inhibition.

SUBMITTER: Hotinger JA

PROVIDER: S-EPMC6963218 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Animal Models of Type III Secretion System-Mediated Pathogenesis.

Hotinger Julia A JA May Aaron E AE

Pathogens (Basel, Switzerland) 20191122 4

The type III secretion system (T3SS) is a conserved virulence factor used by many Gram-negative pathogenic bacteria and has become an important target for anti-virulence drugs. Most T3SS inhibitors to date have been discovered using in vitro screening assays. Pharmacokinetics and other important characteristics of pharmaceuticals cannot be determined with in vitro assays alone. In vivo assays are required to study pathogens in their natural environment and are an important step in the developmen ...[more]

PMID: 31766664

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Project description:The opportunistic pathogen Pseudomonas aeruginosa utilizes an injectisome-type III secretion system (injectisome-T3SS) to elicit cytotoxicity toward epithelial cells and macrophages. Macrophage killing results from the cytotoxic properties of the translocated effector proteins (ExoS, ExoT, ExoU, and ExoY) and inflammasome-mediated induction of pyroptosis. Inflammasome activation can occur following Nlrc4-mediated recognition of cytosolic translocated flagellin (FliC). In the present study, we demonstrate that FliC is a secretion substrate of both the injectisome- and flagellum-associated T3SSs. Molecular analyses indicate that the first 20 amino-terminal residues of FliC are sufficient for secretion by the injectisome-T3SS and that the first 100 residues are sufficient for translocation of FliC into host cells. Although maximal inflammasome activation requires FliC, activation can also occur in the absence of FliC. This prompted us to examine whether other flagellar components might also be translocated into cells to elicit inflammasome activation. Indeed, we find that the flagellar cap (FliD), hook-associated (FlgK and FlgL), hook (FlgE), and rod (FlgE) proteins are secretion substrates of the injectisome-T3SS. None of these proteins, however, result in increased inflammasome activation when they are overexpressed in a fliC mutant and appear to be translocated into host cells. While a role in inflammasome activation has been excluded, these data raise the possibility that flagellar components, which are highly conserved between different bacterial species, trigger other specific host responses from the extracellular milieu or contribute to the pathogenesis of P. aeruginosa.The inflammasome is a host defense mechanism that recognizes invading bacteria and triggers an inflammatory immune response. The opportunistic pathogen P. aeruginosa produces both inflammasome agonists and antagonists. In this study, we demonstrate that overexpression of an agonist suppresses the activity of an antagonist, thereby resulting in inflammasome activation. Since the relative expression levels of agonists and antagonists likely vary between strains, these differences could be important predictors of whether a particular P. aeruginosa strain elicits inflammasome activation.

Dataset Information

Animal Models of Type III Secretion System-Mediated Pathogenesis.

Publications

Animal Models of Type III Secretion System-Mediated Pathogenesis.

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