Concomitant TLR/RLH Signaling of Radioresistant and Radiosensitive Cells Is Essential for Protection against Vesicular Stomatitis Virus Infection

Abstract

Several studies indicated that TLR as well as retinoic acid–inducible gene I–like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)–mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88−/−Trif−/− mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)−/− mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88−/−Trif−/−Cardif−/− (MyTrCa−/−) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor–deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa−/− mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa−/− mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa−/− mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell–derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease.

Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain

“…In contrast, only mice lacking both signaling pathways were unable to produce IFN-␤ in response to challenge with TMEV. A similar observation was made in a recent study with VSV in which both TLRs and RLRs were found to be necessary to mount a protective IFN response (27).…”

Next-Generation Sequencing Reveals a Controlled Immune Response to Zaire Ebola Virus Challenge in Cynomolgus Macaques Immunized with Vesicular Stomatitis Virus Expressing Zaire Ebola Virus Glycoprotein (VSVΔG/EBOVgp)

“…TLRs have been implicated in protection against VSV in both in vivo knockout studies (10) and cell culture of dendritic cells (11) and macrophages (12). The TLRs found to be upregulated (TLR1, TLR6, and TLR10) at D0 have not been reported in the context of VSV, but our data suggest that TLR signaling participates in the immunogenicity of VSV⌬G/EBOVgp, as it has in other vaccines (13).…”

Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

“…Different lines of transgenic mice, all on the C57BL/6 genetic background, were used in the study: WT C57BL/6J mice (Charles River) and several knockout (KO) models: mice deleted for IFN-I receptor (IFNAR-KO) [8], RLR adaptor protein MAVS (MAVS-KO) [9], TLR adaptor protein MyD88 (MyD88-KO) [10], and TLR-3 receptor (TLR3-KO) [11], and mice crossed to bear several deletions, including MyD88/ TRIF-KO, MyD88/MAVS-KO and MyD88/TRIF/MAVS-KO [12].…”