Toll-like receptors (TLRs) are central components of the innate immune system, functioning as pattern recognition receptors that detect microbial- and damage-associated molecular patterns and initiate antimicrobial and inflammatory responses. Beyond the well-established roles in immunity, components of TLR signaling are increasingly recognized as regulators of metabolism, tissue development, and host-microbiome interactions, thereby positioning them at the interface of immunity, physiology, and environmental sensing. The zebrafish (Danio rerio) provides a powerful vertebrate model to study these processes, offering genetic tractability, optical transparency, amenability to germ free techniques, multi-omics profiling, and live imaging.
This thesis investigates the multifaceted roles of TLR2 and its adaptor proteins in metabolism, inflammation, response to mycobacterial infection and host-microbiome interactions using zebrafish larvae as an in vivo model....
Show moreToll-like receptors (TLRs) are central components of the innate immune system, functioning as pattern recognition receptors that detect microbial- and damage-associated molecular patterns and initiate antimicrobial and inflammatory responses. Beyond the well-established roles in immunity, components of TLR signaling are increasingly recognized as regulators of metabolism, tissue development, and host-microbiome interactions, thereby positioning them at the interface of immunity, physiology, and environmental sensing. The zebrafish (Danio rerio) provides a powerful vertebrate model to study these processes, offering genetic tractability, optical transparency, amenability to germ free techniques, multi-omics profiling, and live imaging.
This thesis investigates the multifaceted roles of TLR2 and its adaptor proteins in metabolism, inflammation, response to mycobacterial infection and host-microbiome interactions using zebrafish larvae as an in vivo model. The work presented in this thesis establishes TLR2 as a central coordinator of vertebrate physiology, linking metabolic regulation, inflammatory signaling, infection control, and host-microbiome interactions. We show that TLR2 and its adaptor protein TIRAP maintain glucose homeostasis under unchallenged conditions, couple metabolic state to leukocyte migration during wounding, and especially TLR2 regulates macrophage behavior and dissemination dynamics during nontuberculous mycobacterial infection. Extending beyond immunity, TLR2 also shapes the diversity and functional potential of gut microbiome across developmental stages, highlighting its role as a molecular interface between host metabolism, microbial communities, and immune defense.
Using zebrafish transcriptomic, metabolomic, and gnotobiotic models, this work demonstrates that TLR2 modulates both immune responses and microbial communities, underscoring its potential as a therapeutic target in metabolic disorders, inflammatory diseases, and mycobacterial infections in humans.
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