Host-Pathogen Interactions Made Transparent with the Zebrafish Model

Abstract

The zebrafish holds much promise as a high-throughput drug screening model for immune-related diseases, including inflammatory and infectious diseases and cancer. This is due to the excellent possibilities for in vivo imaging in combination with advanced tools for genomic and large scale mutant analysis. The context of the embryo’s developing immune system makes it possible to study the contribution of different immune cell types to disease progression. Furthermore, due to the temporal separation of innate immunity from adaptive responses, zebrafish embryos and larvae are particularly useful for dissecting the innate host factors involved in pathology. Recent studies have underscored the remarkable similarity of the zebrafish and human immune systems, which is important for biomedical applications. This review is focused on the use of zebrafish as a model for infectious diseases, with emphasis on bacterial pathogens. Following a brief overview of the zebrafish immune system and the tools and methods used to study host-pathogen interactions in zebrafish, we discuss the current knowledge on receptors and downstream signaling components that are involved in the zebrafish embryo’s innate immune response. We summarize recent insights gained from the use of bacterial infection models, particularly the Mycobacterium marinum model, that illustrate the potential of the zebrafish model for high-throughput antimicrobial drug screening.

Galleria mellonella - a novel infection model for the Mycobacterium tuberculosis complex

“…Recently the zebrafish tuberculosis model, using M. marinum , has been used to mimic aspects of LTBI due to its small size, rapid reproduction, formation of granulomas and advanced genetic tools, making it a suitable animal model for large-scale screening of novel therapeutic agents in early-stage preclinical studies. However, zebrafish are anatomically and physiologically different to humans and lack the clinical manifestations and symptoms of tuberculosis disease and moreover they cannot be infected with the pathogenic human strain M. tuberculosis [4,59–62]. …”

Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish

“…Zebrafish have emerged as an excellent model system for the study of vertebrate innate immunity and infectious diseases (36,37). The zebrafish genomes contain orthologs of mammalian TLRs, as well as some fish-specific TLRs (38,39).…”

“…In zebrafish, the innate immune system plays a major role in host defenses against microbial infections in the early stages of life. In their first 4 d of life, zebrafish exhibit no adaptive immune markers; full adaptive immunity does not develop until age 4-6 wk (36,37). Expression of all major components of innate immune system at the very start of development is required for full innate immune function in the early stages of life.…”

Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during zebrafish development

“…Receptors of the innate immune system, called "pattern-recognition receptors," form two well-studied families with huge recognition capacities: the transmembrane Toll-like receptors (TLRs) and the intracytoplasmic Nod-like receptors (10). Their role in sensing is indispensable, and in mammals it is well recognized that all TLRs discovered to date, with the exception of TLR3, signal via their associated adaptor molecule, myeloid differentiation primary response protein 88 (MyD88) (11). Similarly, an almost complete set of TLRs has been described in the pufferfish Fugu rubripes and in the zebrafish Danio rerio (12), and, with the exception of TLR4 (13,14), these TLRs seem to be functional orthologs of mammalian TLRs.…”