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).
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