Amphibian (Xenopus laevis) Macrophage Development and Functionality
Open Access DepositedAmphibians are facing global population declines due to emerging pathogens. In turn, amphibian innate immune cells belonging to the macrophage (M⏀)-lineage are believed to play crucial roles in mitigating many of these infections. Across vertebrates, M⏀ differentiation and functionality are controlled by the principal M⏀ growth factors, colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), both of which signal through the colony stimulating factor-1 receptor (CSF-1R). Through the work presented in this thesis, we highlight several key roles of CSF-1- and IL-34-M⏀s in amphibian (Xenopus laevis) immunity. In contrast to M⏀s, mammalian dendritic cells (DCs) rely on Fms-like tyrosine kinase 3 ligand (FLT3L) for their differentiation, while both M⏀s and DCs share common progenitor populations. Our past work indicates that frog (X. laevis) M⏀s differentiated by the CSF-1 and IL-34 cytokines are morphologically, transcriptionally, and functionally distinct. Moreover, the X. laevis IL34-M⏀s share several features associated with mammalian DCs. To discern the functional implications of this past work, we compared the X. laevis CSF1-M⏀s and IL34-M⏀s, to FLT3L-DCs. The transcriptional and functional data presented in this thesis underscores several shared characteristics between the X. laevis IL34-M⏀s and FLT3L-DCs compared to the CSF1-M⏀s. This includes greater IL34-M⏀s and FLT3L-DCs antigen presentation capacities in vitro and abilities to enhance pathogen re-exposure responses in vivo. Many of the pathogens impacting amphibian species around the globe infect specific developmental stages of these animals. For example, metamorphic and post-metamorphic froglets are particularly susceptible to the Frog Virus 3 (FV3) ranavirus, wherein amphibian M are thought to be central to both the immunity against FV3 as well as the infection strategies of this virus. For this reason, we explored potential differences between pre- and post-metamorphic X. laevis. Indeed, the findings presented in this thesis support our hypothesis that tadpole and post-metamorphic X. laevis CSF-1- and IL34-M⏀s exhibit strikingly distinct cytology and transcriptional profiles, emphasizing the diverse biological roles for these tadpole and frog M⏀ subtypes. In addition to decimating metamorphic and post-metamorphic froglets, the aforementioned FV3 ranavirus establishes chronic infections in older frogs. Accordingly, a major focal point of this thesis work was to establish the contribution of CSF-1- and IL34-M⏀s to these chronic FV3 infections. The frog kidney represents a central FV3 target and we demonstrate that CSF-1-M⏀s exacerbate chronic kidney FV3 infections, leading to increased viral reservoirs and an establishment of an immunosuppressive state within this tissue. In contrast, IL-34-M⏀s offer short-lived protection against FV3 early on during these infections but ultimately do not prevent establishment of chronic FV3 reservoirs. Moreover, our findings indicate that rather than being entirely quiescent, as previously believed, FV3 maintains a low-level active infection during this chronic infection period. Together, this dissertation offers several novel insights into the functional relationship of amphibian M⏀-lineage cells, shedding light on their roles in immune defense, pathogen susceptibility, and chronic infections. We believe that the findings presented here will serve as important platforms for future studies aimed at improving amphibian conservation strategies.
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Dissertation_Hossainey_03.20.2024_-_Muhammad_Riadul_Haque_Hossainey.pdf | 2024-03-28 | Open Access |
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