The Role of the Blood-Brain Barrier during Venezuelan Equine Encephalitis Virus Infection

Abstract

Venezuelan equine encephalitis (VEE) virus is a mosquito-borne alphavirus associated with sporadic outbreaks in human and equid populations in the Western Hemisphere. After the bite of an infected mosquito, the virus initiates a biphasic disease: a peripheral phase with viral replication in lymphoid and myeloid tissues, followed by a neurotropic phase with infection of central nervous system (CNS) neurons, causing neuropathology and in some cases fatal encephalitis. The mechanisms allowing VEE virus to enter the CNS are currently poorly understood. Previous data have shown that the virus gains access to the CNS by infecting olfactory sensory neurons in the nasal mucosa of mice. However, at day 5 after inoculation, the infection of the brain is multifocal, indicating that virus particles are able to cross the blood-brain barrier (BBB). To better understand the role of the BBB during VEE virus infection, we used a well-characterized mouse model system. Using VEE virus replicon particles (VRP), we modeled the early events of neuroinvasion, showing that the replication of VRP in the nasal mucosa induced the opening of the BBB, allowing peripherally administered VRP to invade the brain. Peripheral VEE virus infection was characterized by a biphasic opening of the BBB. Further, inhibition of BBB opening resulted in a delayed viral neuroinvasion and pathogenesis. Overall, these results suggest that VEE virus initially enters the CNS through the olfactory pathways and initiates viral replication in the brain, which induces the opening of the BBB, allowing a second wave of invading virus from the periphery to enter the brain.

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…Paracellular entry under these conditions may contribute to a second phase of CNS infection. Indeed, initial infection of CNS by VEEV via the olfactory route impairs the BBB leading to a CNS infection through hematogenous spread [161]. This observation was further supported by other studies where intracranial inoculation of mice with VEEV replicon particles resulted in increased expression of intercellular adhesion molecule 1 (ICAM-1) on BMECs, followed by BBB disruption [162].…”

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

“…2C), and the production of infectious virus particles (Fig. 2D) were not as elevated as those in BHK21 cells (MOI,5). As a quantitative measurement of the impact of pericytes on the endothelial barrier integrity during the course of JEV infection, we monitored the TEER (Fig.…”

“…Neurotropic virus-associated neuropathy is characterized by the presence of infectious virus particles, immune cells, inflammatory mediators, and eventual neuronal dysfunction or destruction in the parenchymal tissues of the CNS. Generally, BBB integrity is compromised during infection, and this BBB disruption dictates the aforementioned alterations and brain injury in several neurotropic viruses (3)(4)(5)(6). Though most studies demonstrated the detrimental consequences of BBB breakdown during neurotropic virus infection, the opening of the BBB also prevents certain lethal viral CNS infections (7).…”

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

“…RNA samples were then treated with DNase using the Turbo DNA-free kit (Ambion), following the manufacturer's protocol. Quantification of influenza virus strain PR8 hemagglutinin (HA) negative-strand RNA levels in the nasal tissues was performed by reverse transcription-PCR (RT-PCR) as has been described previously (47). Briefly, cDNAs were prepared using reverse transcription with oligo(dT).…”