Characterization of the Innate Host Response to Venezuelan Equine Encephalitis Virus, from the First Infected Cells to System-Wide Modulation In Vivo Public Deposited

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  • March 20, 2019
  • Konopka, Jennifer Lynn
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • The specific host changes induced following viral infection are reflective of the complex interaction occurring between pathogen and host. These changes are often evident in a cascade of altered transcription patterns. However, the elucidation of such cascades in vivo has been limited by a general inability to distinguish changes occurring within the minority of infected cells from that in surrounding uninfected cells. Therefore, an innovative mRNP-tagging system was employed to isolate host mRNA specifically from infected cells following Venezuelan equine encephalitis virus (VEE) infection. To dissect the contributions of autocrine and paracrine signaling events, simultaneous total RNA analysis was utilized in conjunction with this novel approach to directly analyze the infected cell response. The result was a multifaceted profile of the early response to VEE in primary dendritic cells, as well as within the initially targeted tissue in vivo, the draining lymph node. A two-phase innate response to infection was revealed, in which the activation of host genes within infected cells led to the activation of surrounding bystander cells. To further determine the impact of this robust innate immune response on the entire animal, we utilized VEE replicon particles (VRP) to limit infection in vivo to the initially infected cells, and examined the host antiviral response within tissues distal to the site of replication. Although these remote tissues had not encountered VRP, they nevertheless were exposed to high levels of soluble immune modulators, including serum interferon. In the liver and brain, the rapid activation of a panel of interferon-stimulated genes was detected by 3h following VRP footpad inoculation, reaching peak expression levels of greater than 100-fold over mock. Moreover, mice receiving a footpad VRP inoculation 6, 12, or 24h prior to an otherwise lethal VEE challenge were completely protected from death. The results presented here document the rapid modulation of the host innate response within hours of pathogen invasion, a response that is capable of transforming the entire infected animal, and largely determining the outcome of infection.
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  • Johnston, Robert E.
  • Open access

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