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Entry of neurotropic arboviruses into the central nervous system: an in vitro study using mouse brain endothelium
1Department of Pathology, University of Western Australia, Nedlands.
Abstract:
Arbovirus infection of cerebral microvascular endothelial cells was investigated in an in vitro mouse brain endothelial (MBE) cell model. Alphaviruses replicated to a greater extent than did flaviviruses, indicating that viremia may be important in neuroinvasion. Also, some viruses (e.g., Semliki Forest virus) replicated to high titers while others (e.g., Murray Valley encephalitis virus) did not. Viruses that replicated to high titers showed luminal polarity of virus release, indicating that infection of the endothelium may be important in both maintenance of viremia and neuroinvasion; viruses that did not so replicate showed abluminal polarity of release, indicating that virus is actively transported across the endothelial monolayer, another mechanism for neuroinvasion. Infection of MBE cells with highly and less-neuroinvasive strains achieved similar results, indicating that the endothelium does not discriminate between neuroinvasive strains. However, the cerebral microvascular endothelium may be important in discriminating between viruses that invade the brain parenchyma and those that do not: neuron-tropic Ross River virus T48 replicated to higher titers than did ependymal-tropic Ross River virus NB5092. Thus, viruses probably use multiple cellular mechanisms to invade the central nervous system across the cerebral microvascular endothelium.
Insights
Arboviruses invade the brain by infecting endothelial cells. Different virus types and strains exhibit distinct replication and release patterns, suggesting multiple neuroinvasion mechanisms across the blood-brain barrier.
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- Arboviruses pose a significant threat to the central nervous system (CNS).
- The cerebral microvascular endothelium forms the blood-brain barrier (BBB), a critical interface for CNS entry.
- Understanding how arboviruses breach the BBB is crucial for developing effective countermeasures.
Purpose of the Study:
- To investigate arbovirus infection of mouse brain endothelial (MBE) cells in vitro.
- To elucidate the role of the cerebral endothelium in arbovirus neuroinvasion.
- To differentiate mechanisms of neuroinvasion employed by various arboviruses.
Main Methods:
- Utilized an in vitro mouse brain endothelial (MBE) cell model.
- Inoculated MBE cells with different arboviruses, including alphaviruses and flaviviruses.
- Analyzed viral replication titers and release polarity (luminal vs. abluminal).
Main Results:
- Alphaviruses replicated to higher titers than flaviviruses in MBE cells.
- Viruses replicating to high titers showed luminal release, suggesting endothelial involvement in viremia and neuroinvasion.
- Viruses with low replication showed abluminal release, indicating active transport across the endothelium.
- The endothelium did not discriminate between neuroinvasive strains but differentiated between neuron-tropic and ependymal-tropic strains.
Conclusions:
- The cerebral microvascular endothelium plays a multifaceted role in arbovirus neuroinvasion.
- Viruses employ diverse mechanisms, including replication within endothelial cells and active transport, to cross the BBB.
- Endothelial cells may distinguish between viruses that invade brain parenchyma versus those that do not.