Zebrafish (Danio rerio) as a Model System to Investigate the Role of the Innate Immune Response in Human Infectious Diseases

Abstract

The zebrafish (Danio rerio) has emerged as a valuable model for studying host-pathogen interactions due to its unique combination of characteristics. These include extensive sequence and functional conservation with the human genome, optical transparency in larvae that allows for high-resolution visualization of host cell-microbe interactions, a fully sequenced and annotated genome, advanced forward and reverse genetic tools, and suitability for chemical screening studies. Despite anatomical differences with humans, the zebrafish model has proven instrumental in investigating immune responses and human infectious diseases. Notably, zebrafish larvae rely exclusively on innate immune responses during the early stages of development, as the adaptive immune system becomes fully functional only after 4-6 weeks post-fertilization. This window provides a unique opportunity to isolate and examine infection and inflammation mechanisms driven by the innate immune response without the confounding effects of adaptive immunity. In this review, we highlight the strengths and limitations of using zebrafish as a powerful vertebrate model to study innate immune responses in infectious diseases. We will particularly focus on host-pathogen interactions in human infections caused by various bacteria (Clostridioides difficile, Staphylococcus aureus, and Pseudomonas aeruginosa), viruses (herpes simplex virus 1, SARS-CoV-2), and fungi (Aspergillus fumigatus and Candida albicans).

Keywords: animal model; bacteria; fungi; host-pathogen interaction; infectious disease; innate immune response; virus; zebrafish.

Figure 1

Hematopoiesis and development of the immune system in zebrafish. The development of the immune system starts with primitive hematopoiesis at 11 h post-fertilization (hpf). Myeloid and erythroid cells originate in the anterior lateral plate mesoderm (ALPM) and posterior lateral mesoderm (PLPM)). Specifically, myeloid cells develop in the rostral blood islands (RBI) and erythroid cells in the intermediate cell mass (ICM), respectively. At about 2 days post-fertilization (dpf), hematopoietic stem cells (HSCs) appear in the dorsal aorta (DA) and then transit into the caudal hematopoietic tissues (CHT). The terminal phase of hematopoiesis involves the migration of HSCs to the thymus and pronephros (i.e., the first stage of kidney development), where the full maturation of the blood cells occurs. Notably, at 3 dpf zebrafish emerge from the chorion and take contact with the outside environment without fully developed CD4⁺/CD8⁺ lymphocytes, which appear at 3 weeks post-fertilization (wpf).

Figure 2

The innate immune response in zebrafish. The innate immune system is a complex composition of cellular and humoral components. The figure shows the immunity cells, the pattern recognition receptors, and the soluble components that coordinate the diverse innate immunity responses. The figure has been partially generated using the website Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3

Summary of the infection strategies (i.e., immersion, microinjection, and microgavage) used to induce systemic or local infections/intoxication in zebrafish with bacteria, viruses, and fungi [152,157,158,159,160,161,162,163,164,165,166,167,168,169,170].