Injections of Predatory Bacteria Work Alongside Host Immune Cells to Treat Shigella Infection in Zebrafish Larvae

Alexandra R Willis,Christopher Moore,Maria Mazon-Moya,Sina Krokowski,Carey Lambert,Robert Till,Serge Mostowy,R Elizabeth Sockett

doi:10.1016/j.cub.2016.09.067

Alexandra R Willis, Christopher Moore + Show 6 more

Open Access

https://doi.org/10.1016/j.cub.2016.09.067

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Abstract

SummaryBdellovibrio bacteriovorus are predatory bacteria that invade and kill a range of Gram-negative bacterial pathogens in natural environments and in vitro [1, 2]. In this study, we investigated Bdellovibrio as an injected, antibacterial treatment in vivo, using zebrafish (Danio rerio) larvae infected with an antibiotic-resistant strain of the human pathogen Shigella flexneri. When injected alone, Bdellovibrio can persist for more than 24 hr in vivo yet exert no pathogenic effects on zebrafish larvae. Bdellovibrio injection of zebrafish containing a lethal dose of Shigella promotes pathogen killing, leading to increased zebrafish survival. Live-cell imaging of infected zebrafish reveals that Shigella undergo rounding induced by the invasive predation from Bdellovibrio in vivo. Furthermore, Shigella-dependent replication of Bdellovibrio was captured inside the zebrafish larvae, indicating active predation in vivo. Bdellovibrio can be engulfed and ultimately eliminated by host neutrophils and macrophages, yet have a sufficient dwell time to prey on pathogens. Experiments in immune-compromised zebrafish reveal that maximal therapeutic benefits of Bdellovibrio result from the synergy of both bacterial predation and host immunity, but that in vivo predation contributes significantly to the survival outcome. Our results demonstrate that successful antibacterial therapy can be achieved via the host immune system working together with bacterial predation by Bdellovibrio. Such cooperation may be important to consider in the fight against antibiotic-resistant infections in vivo.

Highlights

Injected Predatory Bdellovibrio Persist in Zebrafish Larvae without Ill Effects and Treat Shigella Infection In Vivo The rise in antimicrobial-resistant (AMR) Gram-negative bacterial infections in hospital patients has prompted an urgent search for novel antibacterial agents [3]
Given that Bdellovibrio are ubiquitous in nature, it is likely that these bacteria are already being harmlessly ingested in food or water
The capability of injected Bdellovibrio to treat bacterial infections has not been tested, nor has the interaction of predatory bacteria with leukocytes, and successes here could dramatically expand the therapeutic scope of predatory bacteria against life-threatening infections

Summary

Introduction

Given that Bdellovibrio are ubiquitous in nature, it is likely that these bacteria are already being harmlessly ingested in food or water. For quantification of the survival of Bdellovibrio in vivo, injected larvae were homogenized and predatory bacteria enumerated over time post-infection (Figure 1C).

Results

Conclusion