Zebrafish Embryo Infection Model to Investigate Pseudomonas aeruginosa Interaction With Innate Immunity and Validate New Therapeutics

Abstract

The opportunistic human pathogen Pseudomonas aeruginosa is responsible for a variety of acute infections and is a major cause of mortality in chronically infected patients with cystic fibrosis (CF). Considering the intrinsic and acquired resistance of P. aeruginosa to currently used antibiotics, new therapeutic strategies against this pathogen are urgently needed. Whereas virulence factors of P. aeruginosa are well characterized, the interplay between P. aeruginosa and the innate immune response during infection remains unclear. Zebrafish embryo is now firmly established as a potent vertebrate model for the study of infectious human diseases, due to strong similarities of its innate immune system with that of humans and the unprecedented possibilities of non-invasive real-time imaging. This model has been successfully developed to investigate the contribution of bacterial and host factors involved in P. aeruginosa pathogenesis, as well as rapidly assess the efficacy of anti-Pseudomonas molecules. Importantly, zebrafish embryo appears as the state-of-the-art model to address in vivo the contribution of innate immunity in the outcome of P. aeruginosa infection. Of interest, is the finding that the zebrafish encodes a CFTR channel closely related to human CFTR, which allowed to develop a model to address P. aeruginosa pathogenesis, innate immune response, and treatment evaluation in a CF context.

Localized Infections with P. aeruginosa Strains Defective in Zinc Uptake Reveal That Zebrafish Embryos Recapitulate Nutritional Immunity Responses of Higher Eukaryotes

“…In this regard, it should be highlighted that the development of adaptive immunity is completed only after about 4 weeks post-fertilization. Therefore, the defense against infections in the embryonal state is ensured exclusively by the innate immune system [37]. Although different studies have recently reviewed the…”

“…In this regard, it should be highlighted that the development of adaptive immunity is completed only after about 4 weeks post-fertilization. Therefore, the defense against infections in the embryonal state is ensured exclusively by the innate immune system [ 37 ]. Although different studies have recently reviewed the usefulness of zebrafish for shedding light on fundamental concepts underlying vertebrate immune response to infections by microbial pathogens [ 37 , 38 ], it is not yet known whether the response of zebrafish to infections involves nutritional immunity mechanisms.…”

“…Therefore, the defense against infections in the embryonal state is ensured exclusively by the innate immune system [ 37 ]. Although different studies have recently reviewed the usefulness of zebrafish for shedding light on fundamental concepts underlying vertebrate immune response to infections by microbial pathogens [ 37 , 38 ], it is not yet known whether the response of zebrafish to infections involves nutritional immunity mechanisms. To test this possibility, we have investigated the capability of this basal teleost to contain P. aeruginosa infections by manipulating Zn availability.…”

Zebrafish: an efficient vertebrate model for understanding role of gut microbiota

“…Despite the similarity between humans and zebrafish in immune systems, as discussed in other reviews (Kanther and Rawls 2010 ; Vliegenthart et al 2014 ), zebrafish larvae have no functional adaptive immune system and mostly rely on the innate immune system during the first 2–3 weeks of embryonic development. Hence, zebrafish larvae appear as the effective model for understanding the function of innate immunity when exposed to different bacterial pathogens (Pont and Blanc-Potard 2021 ). For example, zebrafish goblet cells produce mucus to protect intestinal epithelia when encountering pathogens (Martins et al 2019 ).…”

Challenges and opportunities in the development of novel antimicrobial therapeutics for cystic fibrosis

“…It is possible to knock-down the CFTR gene transiently, through the injection of translation-blocking oligonucleotides, or to produce CFTR knockout fish lines. Zebrafish are readily amenable to genetic manipulation and mutant CF lines show evidence of pancreatic dysfunction and haematopoietic defects [72]. Infection of CF zebrafish with P. aeruginosa strain PA14 yielded bacterial populations in early stage of infection that were at 3.5-fold times the density of that seen in wild-type controls.…”