Collaborative Research: Macrophages: Guardians of amphibian skin antifungal defenses

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Fungal infections are a growing wildlife concern because of their devastating effects on biodiversity and ecosystem health. For example, the chytrid fungus, Batrachochytrium dendrobatidis (Bd) infects amphibian skin resulting in the disease chytridiomycosis, which is a leading cause of worldwide amphibian declines and extinctions. Due to its recent appearance, broad host range, and continuing spread into new geographic areas, Bd is regarded as an emerging pathogen. Swimming Bd zoospores colonize the keratinized skin of adult amphibians and the keratinized mouthparts of tadpoles. These invading zoospores develop into urn-shaped zoosporangia in which new zoospores develop and swim out to infect other areas of the skin or new hosts. Unlike other fungal infections that progress to distal organs, Bd remains confined to the skin, causing death by interfering with the essential ion transport across the skin, thereby leading to cardiac arrest. As macrophage-lineage cells, such as Langerhans cells, are integral to skin surveillance and the ensuing immune responses, these cells are undoubtedly important to the antifungal defenses against the skin-localized Bd infections. In turn, the differentiation and functionality of all vertebrate macrophages depend on the colony-stimulating factor-1 receptor (CSF-1R), which is ligated by CSF-1 and the unrelated interleukin-34 (IL-34) cytokines. We previously showed that the Xenopus laevis frog macrophages differentiated by recombinant (r)CSF-1 and rIL-34 possess markedly distinct capacities to recognize and respond to various pathogens. Through these NSF-funded studies, we will examine how these functionally dichotomous frog macrophage subsets contribute to frog Bd susceptibility and resistance. This project will incorporate students at all levels, the PIs will host annual workshops that explore the challenges and opportunities for women and minorities in sciences and public attention will be drawn to the growing threat of Bd through pedagogy and a new collaborative website.The differentiation of Langerhans cells depends on IL-34 while the roles of CSF-1 in these processes remain to be fully defined. Pertinently, enriching X. laevis skin CSF-1-macrophages results in greater Bd susceptibility whereas frogs with more skin IL-34-macrophages exhibit significantly greater resistance against this pathogen. As such, the central hypothesis guiding our studies is that an effective immune response to Bd in the skin depends on an “alarm response” from chytrid-invaded skin cells, which in conjunction with IL-34-macrophages, results in recruitment of other effectors. Conversely, an impaired frog immune response to Bd stems from failure of the skin-resident macrophages and skin epithelial cells to mount appropriate responses due to the production of immunosuppressive factors by the fungus, the infected keratinocytes, and/or resident CSF-1-macrophages. The objectives of our studies are: to define the interactions between amphibian macrophage subsets and Bd; to define the effects of Bd on the interactions between frog macrophages and lymphocytes; and to define the cellular interactions within the frog skin in the context of Bd infections. The in-depth understanding of immune interactions between frog macrophages and Bd granted by our studies, will provide a much-needed perspective into the effectiveness and limitations of the frog immune responses to this deadly fungus.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.