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).

Purpose: This review examines the pathogenic mechanisms of Staphylococcus aureus, emphasizing its toxin-driven virulence factors, including pore-forming toxins, exfoliative toxins, and superantigens. Methods: This paper was conducted using the available literature (PubMed/MEDLINE/Google Scholar and books written by experts in pharmacology and infectious diseases). Results: Toxins are crucial in promoting tissue invasion, immune system evasion, and the development of systemic diseases. Notably, the qualitative and quantitative expression of these toxins influences the clinical presentation and severity of S. aureus infections. The paper explores toxins’ role in S. aureus pathogenesis and clinical manifestations as well as current and emerging therapeutic strategies aimed at targeting these toxins, including antibiotics, monoclonal antibodies, and anti-inflammatory treatments. Additionally, it highlights the potential of novel inhibitors and vaccines to neutralize specific toxins and prevent toxin-mediated diseases. Conclusion: By combining antimicrobial therapies with approaches that neutralize toxins and modulate the immune response, clinicians can improve outcomes in patients affected by S. aureus infections.

Osteosarcoma (OS), the most common primary malignant bone tumor arising in the highly mechanosensitive bone tissue, exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. In this study, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that the highly aggressive U-2 OS cell model undergoes TRPV1-dependent perpendicular reorientation, in contrast to the inert response observed in the less aggressive SAOS-2 cells. Through confocal microscopy, immunohistochemistry, and atomic force microscopy, we demonstrate that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically replicate the mechanical phenotype, altering metastatic traits such as cell adhesion, edge architecture, migration rate, nuclear-to-cytoplasmic ratio, and chemotherapeutic sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, elicits subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the pro-to-oncogene Src in U-2 OS versus SAOS-2 cells. Parallel changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 as a molecular switch in the Src–acH3 mechanosignaling axis. These TRPV1-mediated effects were not observed in non-malignant cells, underscoring their tumor specificity. Our findings position TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, offering a potential therapeutic target—particularly in aggressive, drug-resistant subtypes.

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes