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bioRxiv · 10.1101/2023.06.30.547169

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezualen Equine Encephalitis virus within olfactory sensory neurons

Klein, R. S.·Cain, M. D.·Klein, N. R.·Jiang, X.
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Abstract

Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Here, we utilized an established murine model of intranasal infection with VEEV to assess the cellular targets and IFN signaling responses after VEEV exposure. We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 hours during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFN triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFN treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFN for the treatment of human encephalitic alphavirus exposures. AUTHOR SUMMARYVenezuelan Equine Encephalitis virus (VEEV) may enter the brain through the nasal cavity upon intranasal exposure. The nasal cavity normally displays brisk antiviral immune responses, thus it is unclear why this type of exposure leads to fatal VEEV infection. Using an established murine model of intranasal infection with VEEV we identified the initial targets of infection within the nasal cavity and found that antiviral immune responses to virus at this site and during brain infection are delayed for up to 48 hours. Thus, administration of a single intranasal dose of recombinant IFN at the time of or early after infection improved early antiviral immune responses and suppressed viral replication, which delayed onset of brain infection and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the nasal cavity, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFN for the treatment of human VEEV exposures.

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Klein, R. S., Cain, M. D., Klein, N. R., Jiang, X.. 2023-06-30. Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezualen Equine Encephalitis virus within olfactory sensory neurons. https://doi.org/10.1101/2023.06.30.547169

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