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The chytrid fungus, Batrachochytrium dendrobatidis (Bd), infects amphibian skin, causing chytridiomycosis, which is a contributing cause of worldwide declines and extinctions of amphibians. Relatively little is known about the roles of amphibian skin-resident immune cells, such as macrophages, in these antifungal defenses. Across vertebrates, macrophage differentiation is controlled through the activation of colony-stimulating factor-1 (CSF1) receptor by CSF1 and interleukin-34 (IL34) cytokines. While the precise roles of these respective cytokines in macrophage development remain to be fully explored, our ongoing studies indicate that frog (Xenopus laevis) macrophages differentiated by recombinant forms of CSF1 and IL34 are functionally distinct. Accordingly, we explored the roles of X. laevis CSF1- and IL34-macrophages in anti-Bd defenses. Enriching cutaneous IL34-macrophages, but not CSF1-macrophages, resulted in significant anti-Bd protection. In vitro analysis of frog macrophage-Bd interactions indicated that both macrophage subsets phagocytosed Bd. However, IL34-macrophages cocultured with Bd exhibited greater pro-inflammatory gene expression, whereas CSF1-macrophages cocultured with Bd showed greater immunosuppressive gene expression profiles. Concurrently, Bd-cocultured with CSF1-macrophages, but not IL34-macrophages, possessed elevated expression of genes associated with immune evasion. This work marks a step forward in our understanding of the roles of frog macrophage subsets in antifungal defenses. 

Amphibian metamorphosis represents a dramatic example of post-embryonic development. In the anuran Xenopus laevis frog, this process involves extensive changes to larval tissues, structures, and physiology to produce its adult form. As a long-standing model to study tissue remodeling, both amphibian metamorphosis and mammalian development are under the control of thyroid hormone. Successful remodeling though, also requires precise temporospatial regulation of immune activation. Yet there is much to learn about the immune components linked to metamorphosis. In turn, granulocytes are a class of innate immune cells recently touted for their participation in processes beyond classical immune defenses, including in pathological and non-pathological tissue remodeling. In this manuscript, we explore the roles of granulocytes in perhaps the most conspicuous anuran metamorphic event: tadpole tail reabsorption. We characterize granulocyte infiltration into the tail as metamorphosis progresses. Although some granulocyte subpopulations exist in both Xenopus and mammals, our previous work has identified additional Xenopus-specific populations. Thus, here we further explored subpopulation dynamics through distinct stages of natural metamorphosis, their likely roles during this process, and their relationship with thyroid hormone. As endocrine disruptors continue to threaten species across the animal kingdom, the work described here offers much-needed insight into immune contributions to endocrine-linked development. 

Global amphibian declines are compounded by deadly disease outbreaks caused by the chytrid fungus,Batrachochytrium dendrobatidis(Bd). Much has been learned about the roles of amphibian skin-produced antimicrobial components and microbiomes in controllingBd, yet almost nothing is known about the roles of skin-resident immune cells in anti-Bddefenses. Mammalian mast cells reside within and serve as key immune sentinels in barrier tissues like skin. Accordingly, we investigated the roles ofXenopus laevisfrog mast cells duringBdinfections. Our findings indicate that enrichment ofX. laevisskin mast cells confers anti-Bdprotection and ameliorates the inflammation-associated skin damage caused byBdinfection. This includes a significant reduction in infiltration ofBd-infected skin by neutrophils, promoting mucin content within cutaneous mucus glands, and preventingBd-mediated changes to skin microbiomes. Mammalian mast cells are known for their production of the pleiotropic interleukin-4 (IL4) cytokine and our findings suggest that theX. laevisIL4 plays a key role in manifesting the effects seen following cutaneous mast cell enrichment. Together, this work underscores the importance of amphibian skin-resident immune cells in anti-Bddefenses and illuminates a novel avenue for investigating amphibian host–chytrid pathogen interactions. 

Macrophage (Mϕ)-lineage cells are integral to the immune defences of all vertebrates, including amphibians. Across vertebrates, Mϕdifferentiation and functionality depend on activation of the colony stimulating factor-1 (CSF1) receptor by CSF1 and interluekin-34 (IL34) cytokines. Our findings to date indicate that amphibian (Xenopus laevis) Mϕs differentiated with CSF1 and IL34 are morphologically, transcriptionally and functionally distinct. Notably, mammalian Mϕs share common progenitor population(s) with dendritic cells (DCs), which rely on fms-like tyrosine kinase 3 ligand (FLT3L) for differentiation whileX. laevisIL34-Mϕs exhibit many features attributed to mammalian DCs. Presently, we comparedX. laevisCSF1- and IL34-Mϕs with FLT3L-derivedX. laevisDCs. Our transcriptional and functional analyses indicated that indeed the frog IL34-Mϕs and FLT3L-DCs possessed many commonalities over CSF1-Mϕs, including transcriptional profiles and functional capacities. Compared toX. laevisCSF1-Mϕs, the IL34-Mϕs and FLT3L-DCs possess greater surface major histocompatibility complex (MHC) class I, but not MHC class II expression, were better at eliciting mixed leucocyte responsesin vitroand generatingin vivore-exposure immune responses againstMycobacterium marinum. Further analyses of non-mammalian myelopoiesis akin to those described here, will grant unique perspectives into the evolutionarily retained and diverged pathways of Mϕand DC functional differentiation. This article is part of the theme issue ‘Amphibian immunity: stress, disease and ecoimmunology’. 

Global amphibian declines are largely driven by deadly disease outbreaks caused by the chytrid fungus, Batrachochytrium dendrobatidis (Bd). In the time since these disease outbreaks were first discovered, much has been learned about the roles of amphibian skin-produced antimicrobial components and skin microbiomes in controlling Bd. Yet almost nothing is known about the roles of skin-resident immune cells in anti-Bd defenses. Notably, mammalian mast cells reside within and serve as key immune sentinels in barrier tissues like the skin. Thus, they are critical to immune recognition of pathogens and to orchestrating the ensuing immune responses. Accordingly, we investigated the roles of Xenopus laevis frog mast cells during Bd infections. Our findings indicate that enrichment of X. laevis skin mast cells confers significant anti-Bd protection and ameliorates the inflammation-associated skin damage caused by Bd infection. Moreover, enriching X. laevis mast cells promotes greater mucin content within cutaneous mucus glands and protects frogs from Bd-mediated changes to their skin microbiomes. Together, this work underlines the importance of amphibian skin-resident immune cells in anti-Bd defenses and introduces a novel approach for investigating amphibian host-chytrid pathogen interactions.