Abstract
Infections by ranaviruses such as Frog virus 3 (Fv3), are significantly contributing to worldwide amphibian population declines. Notably, amphibian macrophages (Mφs) are important to both the Fv3 infection strategies and the immune defense against this pathogen. However, the mechanisms underlying amphibian Mφ Fv3 susceptibility and resistance remain unknown. Mφ differentiation is mediated by signaling through the colony-stimulating factor-1 receptor (CSF-1R) which is now known to be bound not only by CSF-1, but also by the unrelated interleukin-34 (IL-34) cytokine. Pertinently, amphibian (Xenopus laevis) Mφs differentiated by CSF-1 and IL-34 are highly susceptible and resistant to Fv3, respectively. Accordingly, in the present work, we elucidate the facets of this Mφ Fv3 susceptibility and resistance. Because cellular resistance to viral replication is marked by expression of antiviral restriction factors, it was intuitive to find that IL-34-Mφs possess significantly greater mRNA levels of select restriction factor genes than CSF-1-Mφs. Xenopodinae amphibians have highly expanded repertoires of antiviral interferon (IFN) cytokine gene families, and our results indicated that in comparison with the X. laevis CSF-1-Mφs, the IL-34-Mφs express substantially greater transcripts of representative IFN genes, belonging to distinct gene family clades, as well as their cognate receptor genes. Finally, we demonstrate that IL-34-Mφ-conditioned supernatants confer IFN-mediated anti-Fv3 protection to the virally susceptible X. laevis kidney (A6) cell line. Together, this work underlines the differentiation pathways leading to Fv3-susceptible and -resistant amphibian Mφ populations and defines the molecular mechanisms responsible for these differences.
Highlights
Infections by ranaviruses such as Frog virus 3 (Fv3), are significantly contributing to worldwide amphibian population declines
As M differentiation depends on the activation of the colony-stimulating factor-1 (CSF-1) receptor, it is compelling that in addition to CSF-1 [7,8,9,10], this receptor may be engaged by the unrelated interleukin-34 (IL-34) [11,12,13,14], presumably contributing to the functional heterogeneity seen across vertebrate Ms
We previously demonstrated that X. laevis Ms differentiated with IL-34 are resistant to Fv3 infection, whereas CSF-1derived Ms are significantly more susceptible to this virus [5, 6]
Summary
Whereas the expression of some of these restriction factors is enhanced by IFNs, others are constitutively expressed (24 –27). To delineate the mechanisms responsible for IL-34 – derived M antiviral resistance, and CSF-1-differentiated M susceptibility to Fv3, we compared these cell populations for their gene expression of select intron-containing and intronless type I and type III IFNs as well as the respective IFN receptor genes. We examined the restriction factor gene expression levels of these M populations and compared the ability of Fv3 to replicate within CSF- and IL-34 – derived Ms. We examined the ability of CSF-1-M– and IL-34-M– conditioned supernatants to restrict Fv3 growth in an otherwise highly Fv3-susceptible X. laevis kidney epithelial cell line (A6)
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