Abstract
Infections by Frog Virus 3 (FV3) and other ranavirus genus members are significantly contributing to global amphibian decline. The Xenopus laevis frog is an ideal research platform upon which to study the roles of distinct frog leukocyte populations during FV3 infections. Frog macrophages (MΦs) are integrally involved during FV3 infection, as they facilitate viral dissemination and persistence but also participate in immune defense against this pathogen. In turn, MΦ differentiation and functionality depend on the colony-stimulating factor-1 receptor (CSF-1R), which is ligated by CSF-1 and iterleukin-34 (IL-34) cytokines. Our past work indicated that X. laevis CSF-1 and IL-34 give rise to morphologically and functionally distinct frog MΦ subsets, and that these CSF-1- and IL-34-MΦs respectively confer susceptibility and antiviral resistance to FV3. Because FV3 targets the frog kidneys and establishes chronic infections therein, presently we examined the roles of the frog CSF-1- and IL-34-MΦs in seeding and maintaining these chronic kidney infections. Our findings indicate that the frog CSF-1-MΦs result in more prominent kidney FV3 infections, which develop into greater reservoirs of lingering FV3 marked by infiltrating leukocytes, fibrosis, and overall immunosuppressive states. Moreover, the antiviral effects of IL-34-MΦs are short-lived and are lost as FV3 infections progress.
Highlights
The diseases and population die-offs associated with amphibian infections by Frog Virus 3 (FV3) and other members of the genus Ranavirus are contributing to global amphibian population declines [1,2,3,4,5,6]
While anuran amphibian hosts are able to clear the primary FV3 infections, residual virus persists within the frog kidneys and myeloid populations [9,10,11], presumably rendering the animals harboring this virus as reservoirs and sources of environmental dissemination of the pathogen
MΦ lineage-commitment, differentiation, survival, and functionality are controlled by the colony-stimulating factor-1 (CSF-1; M-CSF) receptor [15,16,17], which is ligated by CSF-1 and interleukin-34 (IL-34) cytokines/growth factors [18,19]
Summary
The diseases and population die-offs associated with amphibian infections by Frog Virus 3 (FV3) and other members of the genus Ranavirus (family Iridoviridae) are contributing to global amphibian population declines [1,2,3,4,5,6]. While anuran (frogs/toads) amphibian hosts are able to clear the primary FV3 infections, residual virus persists within the frog kidneys and myeloid populations [9,10,11], presumably rendering the animals harboring this virus as reservoirs and sources of environmental dissemination of the pathogen. MΦs are important to recognizing and coordinating antiviral responses [12], MΦs are commonly targeted by disparate viruses in establishing long-term viral reservoirs during chronic viral infections [13,14]. Using the Xenopus laevis frog model, we previously established that amphibian MΦs differentiated by IL-34 offer anti-FV3 protection, whereas CSF-1-MΦs render the animals significantly more susceptible to FV3 infections [7]. We examine the roles played by the frog IL-34- and CSF-1-MΦs during chronic FV3 infections and establish the immunological parameters affected by skewing these frog MΦ populations during infections with this ranavirus pathogen
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