Abstract
Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169+ subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7−/− mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7−/− mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7−/− mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies.
Highlights
Vesicular stomatitis virus (VSV) is a prototypic member of the Rhabdovirus family that consists of neurotropic viruses including Rabies virus
Since VSV is an arthropod borne virus, we explored the spread of VSV from the skin, its entry site, to the central nervous system (CNS) and investigated the function of Toll-like receptor-7 (TLR7) signaling in viral control
VSV-luciferase infection, and the virus was detectable in the brain and spinal cord of paralyzed myeloid differentiation primary response gene 88 (MyD88)−/− mice using the in vivo imaging system (Supplementary Figure 1A) with computed tomography (Supplementary Figure 1B)
Summary
Vesicular stomatitis virus (VSV) is a prototypic member of the Rhabdovirus family that consists of neurotropic viruses including Rabies virus. The neurotropism exhibited by VSV causes paralytic symptoms in mammals, including mice It serves as an ideal model for investigating immunity to human neurotropic viruses like rabies virus [5]. Immune protection and host survival are strongly determined by the induction of an efficient type-I interferon (IFN) response [7, 8]. This response is strictly regulated by viral sensing pattern recognition receptors (PRRs), mainly endosomal Toll-like receptor-7 (TLR7), and cytosolic retinoic acid–inducible gene I (RIG-I) receptors [9, 10].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
