Mechanism of Neuroinvasion of Venezuelan Equine Encephalitis Virus in the Mouse

Abstract

Venezuelan equine encephalitis virus (VEE) causes a biphasic disease in mice following subcutaneous inoculation in the footpad. In the initial phase, virus replicates primarily in the lymphoid tissues and induces a high titer viremia. Subsequently, the virus invades the central nervous system (CNS) from the circulation, and an encephalitis ensues. At the earliest times that VEE specific in situ hybridization signal was observed in the CNS, it was in areas of the brain involved in olfaction, leading to the hypothesis that virus may invade the brain from the circulation through the olfactory system. The results presented in this paper define the route of CNS invasion in experimental murine VEE disease initiated by subcutaneous inoculation. Virus circulating in the blood appears to seed specific areas of the peripheral nervous system during the viremic lymphoid phase of the illness. Virus replication within olfactory and dental tissues is followed by centripetal spread of virus along neural pathways. Virus enters the brain in a pattern reflecting the proximity of the peripheral invasion site to the CNS. Specifically, virus is first found in the brain within the structures of the olfactory system, followed by areas innervated by the trigeminal nerve. Virus later disseminates along fiber tracts and connected circuits within the brain, resulting in a disseminated meningoencephalitis. Surgical or chemical interruption of the olfactory system at the level of the olfactory neuroepithelium or the main olfactory bulb inhibited entry of VEE into the CNS through the olfactory nerve. However, the olfactory route is not absolutely required for CNS invasion, as virus invaded the CNS of olfactory ablated animals through the trigeminal nerve. These observations are consistent with a model of hematogenous seeding of the peripheral nervous system, followed by invasion of the CNS by direct neural spread.

Recombinant Semliki Forest virus vaccine vectors: the route of injection determines the localization of vector RNA and subsequent T cell response

“…20 However, the rSFV in our study was strictly non-spreading and suicidal and therefore entry into the CNS could not have occurred by the virus replicating through the brain-blood barrier. Entry of the non-spreading virus could in the present study have occurred either by passage across cerebral EC, 21 or via olfatory and trigemial nerves 22 or through migration of virally infected leukocytes. 23 An argument against at least the latter explanation is that blood was found negative for vector transcripts.…”

“…Splenocytes were used for tetramer staining and a fraction was set up in culture for in vitro restimulation with NP 147-155 peptide ((TYQRTRALV), KJ Ross-Petersen, Horsholm, Denmark) in the presence of autologous irradiated (25 Gy) naive splenocytes as feeder cells (at a 1:0.7 ratio) for 5 days, in IMDM medium (Gibco BRL) supplemented with 10% FCS, 2 mm glutamine, 100 g/ml streptomycin and 100 IU/ml penicillin and 50 m 2-mercaptoethanol. The CTL assay was performed on P815 target cells labeled with 100 Ci 51 Cr and loaded with NP 147-155 peptide (50 m) or with P198 [14][15][16][17][18][19][20][21][22] control peptide, at three different effector:target (E:T) ratios. After incubation for 4 h, supernatants were collected and radioactivity measured in a ␥ counter.…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…CNS invasion via olfactory bulb has been demonstrated for several encephalitic arboviruses, including SLEV [142], MVEV [143], VEEV [144], EEEV [145], and LACV [146]. Soon after onset of viremia, viral particles exit the fenestrated capillaries beneath the mucosa of the nasal cavity.…”

“…OSNs reside in the olfactory neuroepithelium with dendritic terminals that project into the nasal cavity and axonal projections that extend the cribiform plate into the glomerular structures of the olfactory bulb, thereby providing an axonal pathway for neurotropic viruses to gain access to the CNS. Infection of OSNs is followed by viral spread into the olfactory bulb via the anterograde axonal pathway [142,144]. Once inside the olfactory bulb, the virus disseminates rapidly to the brain tissues.…”

Genetically engineered, live attenuated vaccines for Venezuelan equine encephalitis: testing in animal models

“…However, severe neurological infection, including fatal encephalitis, is common in infections of rodents [2,3] and horses [4], and can occur in humans, typically children [5]. Although natural disease is usually acquired through mosquito bite, VEEV is highly infectious as an aerosol and has caused many laboratory infections by this route [6].…”