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Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis.

ABSTRACT: Ranaviruses such as frog virus 3 ([FV3] family Iridoviridae) are increasingly prevalent pathogens that infect reptiles, amphibians, and fish worldwide. Whereas studies in the frog Xenopus laevis have revealed the critical involvement of CD8 T-cell and antibody responses in host resistance to FV3, little is known about the role played by innate immunity to infection with this virus. We have investigated the occurrence, composition, activation status, and permissiveness to infection of peritoneal leukocytes (PLs) in Xenopus adults during FV3 infection by microscopy, flow cytometry, and reverse transcription-PCR. The total number of PLs and the relative fraction of activated mononucleated macrophage-like cells significantly increase as early as 1 day postinfection (dpi), followed by NK cells at 3 dpi, before the peak of the T-cell response at 6 dpi. FV3 infection also induces a rapid upregulation of proinflammatory genes including arginase 1, interleukin-1beta, and tumor necrosis factor alpha. Although PLs are susceptible to FV3 infection, as evidenced by apoptotic cells, active FV3 transcription, and the detection of viral particles by electron microscopy, the infection is weaker (fewer infectious particles), more transitory, and involves a smaller fraction (less than 1%) of PLs than the kidney, the main site of infection. However, viral DNA remains detectable in PLs for at least 3 weeks postinfection, past the point of viral clearance observed in the kidneys. This suggests that although PLs are actively involved in anti-FV3 immune responses, some of these cells can be permissive and harbor quiescent, asymptomatic FV3.

SUBMITTER: Morales HD

PROVIDER: S-EPMC2863837 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis.

Morales Heidi D HD Abramowitz Lara L Gertz Jacqueline J Sowa Jessica J Vogel Ashley A Robert Jacques J

Journal of virology 20100303 10

Ranaviruses such as frog virus 3 ([FV3] family Iridoviridae) are increasingly prevalent pathogens that infect reptiles, amphibians, and fish worldwide. Whereas studies in the frog Xenopus laevis have revealed the critical involvement of CD8 T-cell and antibody responses in host resistance to FV3, little is known about the role played by innate immunity to infection with this virus. We have investigated the occurrence, composition, activation status, and permissiveness to infection of peritoneal ...[more]

PMID: 20200236

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Project description:UnlabelledRanaviruses (Iridoviridae) are posing an increasing threat to amphibian populations, with anuran tadpoles being particularly susceptible to these viral infections. Moreover, amphibians are the most basal phylogenetic class of vertebrates known to possess both type I and type III interferon (IFN)-mediated immunity. Moreover, little is known regarding the respective roles of the IFN mediators in amphibian antiviral defenses. Accordingly, we transcriptionally and functionally compared the amphibian Xenopus laevis type I (IFN) and III (IFN-λ) IFNs in the context of infections by the ranavirus frog virus 3 (FV3). X. laevis IFN and IFN-λ displayed distinct tissue expression profiles. In contrast to our previous findings that X. laevis tadpoles exhibit delayed and modest type I IFN responses to FV3 infections compared to the responses of adults, here we report that tadpoles mount timely and robust type III IFN gene responses. Recombinant forms of these cytokines (recombinant X. laevis IFN [rXlIFN] and rXlIFN-λ) elicited antiviral gene expression in the kidney-derived A6 cell line as well as in tadpole leukocytes and tissues. However, rXlIFN-λ was less effective than rXlIFN in preventing FV3 replication in A6 cells and tadpoles and inferior at promoting tadpole survival. Intriguingly, FV3 impaired A6 cell and tadpole kidney type III IFN receptor gene expression. Furthermore, in A6 cultures rXlIFN-λ conferred equal or greater protection than rXlIFN against recombinant viruses deficient for the putative immune evasion genes, the viral caspase activation and recruitment domain (vCARD) or a truncated vIF-2α gene. Thus, in contrast to previous assumptions, tadpoles possess intact antiviral defenses reliant on type III IFNs, which are overcome by FV3 pathogens.ImportanceAnuran tadpoles, including those of Xenopus laevis, are particularly susceptible to infection by ranavirus such as FV3. We investigated the respective roles of X. laevis type I and type III interferons (IFN and IFN-λ, respectively) during FV3 infections. Notably, tadpoles mounted timely and more robust IFN-λ gene expression responses to FV3 than adults, contrasting with the poorer tadpole type I IFN responses. However, a recombinant X. laevis IFN-λ (rXlIFN-λ) conferred less protection to tadpoles and the A6 cell line than rXlIFN, which may be explained by the FV3 impairment of IFN-λ receptor gene expression. The importance of IFN-λ in tadpole anti-FV3 defenses is underlined by the critical involvement of two putative immune evasion genes in FV3 resistance to IFN- and IFN-λ-mediated responses. These findings challenge the view that tadpoles have defective antiviral immunity and suggest, rather, that their antiviral responses are predominated by IFN-λ responses, which are overcome by FV3.

Project description:UnlabelledThe increasing prevalence of ranavirus (RV; Iridoviridae) infections of wild and commercially maintained aquatic species is raising considerable concerns. While Xenopus laevis is the leading model for studies of immunity to RV, amphibian antiviral interferon (IFN) responses remain largely uncharacterized. Accordingly, an X. laevis type I interferon was identified, the expression of the gene for this IFN was examined in RV (frog virus 3 [FV3])-infected tadpoles and adult frogs by quantitative PCR, and a recombinant form of this molecule (recombinant X. laevis interferon [rXlIFN]) was produced for the purpose of functional studies. This rXlIFN protected the kidney-derived A6 cell line and tadpoles against FV3 infection, decreasing the infectious viral burdens in both cases. Adult frogs are naturally resistant to FV3 and clear the infection within a few weeks, whereas tadpoles typically succumb to this virus. Hence, as predicted, virus-infected adult X. laevis frogs exhibited significantly more robust FV3-elicited IFN gene expression than tadpoles; nevertheless, they also tolerated substantially greater viral burdens following infection. Although tadpole stimulation with rXlIFN prior to FV3 challenge markedly impaired viral replication and viral burdens, it only transiently extended tadpole survival and did not prevent the eventual mortality of these animals. Furthermore, histological analysis revealed that despite rXlIFN treatment, infected tadpoles had considerable organ damage, including disrupted tissue architecture and extensive necrosis and apoptosis. Conjointly, these findings indicate a critical protective role for the amphibian type I IFN response during ranaviral infections and suggest that these viruses are more pathogenic to tadpole hosts than was previously believed, causing extensive and fatal damage to multiple organs, even at very low titers.ImportanceRanavirus infections are threatening wild and commercially maintained aquatic species. The amphibian Xenopus laevis is extensively utilized as an infection model for studying ranavirus-host immune interactions. However, little is known about amphibian antiviral immunity and, specifically, type I interferons (IFNs), which are central to the antiviral defenses of other vertebrates. Accordingly, we identified and characterized an X. laevis type I interferon in the context of infection with the ranavirus frog virus 3 (FV3). FV3-infected adult frogs displayed more robust IFN gene expression than tadpoles, possibly explaining why they typically clear FV3 infections, whereas tadpoles succumb to them. Pretreatment with a recombinant X. laevis IFN (rXlIFN) substantially reduced viral replication and infectious viral burdens in a frog kidney cell line and in tadpoles. Despite reducing FV3 loads and extending the mean survival time, rXlIFN treatments failed to prevent tadpole tissue damage and mortality. Thus, FV3 is more pathogenic than was previously believed, even at very low titers.

Dataset Information

Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis.

Publications

Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis.

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