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Septins restrict inflammation and protect zebrafish larvae from Shigella infection.

ABSTRACT: Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15-depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation.

SUBMITTER: Mazon-Moya MJ

PROVIDER: S-EPMC5507465 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Septins restrict inflammation and protect zebrafish larvae from Shigella infection.

Mazon-Moya Maria J MJ Willis Alexandra R AR Torraca Vincenzo V Boucontet Laurent L Shenoy Avinash R AR Colucci-Guyon Emma E Mostowy Serge S

PLoS pathogens 20170626 6

Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial in ...[more]

PMID: 28650995

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Project description:Colonization resistance, i.e., the protective effects of associated microbiota for the animal host against pathogen infection, has been studied widely over the last 100 years. However, few molecules mediating colonization resistance have been identified. In the symbiosis formed by Delia antiqua and its associated microbes, six bacteria protect larvae from infection with the entomopathogen Beauveria bassiana, providing an ideal model to investigate the chemical mechanism for colonization resistance. Subsequently using this symbiotic system, we first compared effects of the six bacterial species, and one control bacterium (Klebsiella oxytoca) that showed no antifungal effects, on B. bassiana and its infection of D. antiqua Second, metabolomic profiles of the six bacteria and K. oxytoca were compared to identify candidate metabolites that may prevent infection. Third, the concentrations of candidate metabolites in situ from axenic and nonaxenic larvae were determined. Finally, effects of artificial metabolite cocktails on B.bassiana and its infection of D. antiqua larvae were determined. Results showed that compared to K. oxytoca, the six bacteria produced a metabolite cocktail showing inhibitory effects on conidial germination, mycelial growth of B.bassiana, and fungal infection. Our work revealed novel molecules that mediate colonization resistance, which could help in developing chemical mechanisms of colonization resistance. Moreover, this work may aid in discovery and expansion of new bioactive antibiotics, promoting development of prophylactic and therapeutic approaches for treating infectious diseases.IMPORTANCE The protection of associated microbiota for their animal hosts against pathogen infection has been studied widely over the last 100 years. However, how those microbes protect the animal host remains unclear. In former studies, body surface microbes of one insect, Delia antiqua, protected the insect larvae from infection with the entomopathogen Beauveria bassiana By comparing the metabolites produced by microbes that protect the insect and microbes that cannot protect the insect, the question of how the microbes protect the insect is answered. It turns out that body surface bacteria produce a metabolite cocktail that inhibits colonization of B.bassiana and consequently protects the insect. This work reveals novel molecules with antifungal activity, which may aid in discovery and expansion of new prophylactic and therapeutic natural chemicals for treating infectious diseases.

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Septins restrict inflammation and protect zebrafish larvae from Shigella infection.

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Septins restrict inflammation and protect zebrafish larvae from Shigella infection.

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