CAREER: The roles of amphibian macrophages in susceptibility and immunological resistance to the Frog Virus 3 ranavirus

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Frog populations around the globe are declining with almost two-thirds of all frog species threatened with extinction. Viral infections, such as Frog Virus 3, are significant contributors to these declines. Tadpoles are far more susceptible to viruses than adult frogs. There is a need to better understand the immune mechanisms that dictate susceptibility and resistance to Frog Virus 3. Such knowledge could be used to prevent further decline in frog populations. In this respect, it is notable that immune cells known as 'macrophages' are important both for the virus to infect the frog and for the frog's immune response against the infection. This award will define how distinct populations of macrophages found in the tadpole and adult frog serve either as immune barriers to this virus or as gateways for Frog Virus 3 entry, dissemination to other parts of the body, persistence and spread to other frogs. This work will broaden understanding of how vertebrates, including humans, resist viral infections and potentially lead to new therapies against viral diseases in humans. In addition, it will increase knowledge of conservation issues in the local community and provide educational opportunities to students, including underrepresented minorities, at all educational levels.The differentiation of nearly all vertebrate macrophages studied to date depends on the macrophage colony-stimulating factor (M-CSF) receptor. It is activated by both the M-CSF ligand and the interleukin34 (IL-34) cytokine. In Xenopus laevis, macrophages derived by M-CSF exacerbate Frog Virus 3 infections in the tadpole and adult frog whereas macrophages derived by IL-34 confer anti-viral resistance. In, Xenopus laevis, as in other vertebrates, the major antiviral effectors of IL-34-stimulated macrophages appear to be interferons. Interestingly, amphibians possess an expanded repertoire of interferons. Different subsets of these interferons are stimulated in tadpoles and adult frogs, in response to Frog Virus 3 infection, suggesting that different subsets of macrophages respond differently to Frog Virus 3. This award will (1) elucidate the roles played by M-CSF-stimulated and IL-34-stimulated macrophages in susceptibility and resistance to Frog Virus 3, (2) characterize the anti-Frog Virus 3 capacities of the distinct interferon subsets produced by the two macrophage populations. This work could foster development of measures to counteract amphibian declines by enhancing frog resistance to viral infections or using interferon treatment to prevent Frog Virus 3 replication. Moreover, as there are many parallels between the amphibian and mammalian immune systems, this research could deepen the understanding of how the human immune system evolved and lead to new ways for treating human viral infections. This award supports outreach aimed at raising public awareness of amphibian conservation. It provides hands-on laboratory experience to local high school and undergraduates, including underrepresented minorities, and mentors graduate students and postdoctoral fellows.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.