Optimisation of a flow-based human in vitro blood–brain barrier model to replace animal models for studying immunopathogenesis of viral brain infections

Aims

This project aims to develop a human cell-culture model of the blood–brain barrier, to replace the use of some animal studies.

Background

Encephalitis (inflammation and swelling of the brain) can be caused by a range of viruses, and the results are usually devastating. The blood‒brain barrier (BBB) is the specialised barrier that prevents viruses, bacteria and toxins from entering the brain, and a number of studies have implicated a disruption of the BBB during encephalitis. However, most studies of the BBB are done in animals or animal cell lines; most commonly rat and mouse models. These animals have symptoms such as leg paralysis, hunched back, and seizures following infection. A model of the BBB using human cells would represent an important scientific advance and replace the use of some animals used in BBB experiments.

Research details and methods

Building on existing 2D cultures, a 3D flow-based model which mimics blood flow in brain capillaries will be developed and characterised. Primary or immortalised human brain endothelial cells will be seeded on the blood side of the model and astrocytes or pericytes on the brain side. Serum from patients will be pumped over the cells and viruses will be introduced to the system to simulate infection and investigate the role of the BBB.

Patabendige A et al (2018). Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model. Molecular and Cellular Neuroscience 89: 60-70. doi: 10.1016/j.mcn.2018.04.002

Ferguson MC et al. (2015). Ability of the encephalitic arbovirus semliki forest virus to cross the blood-brain barrier is determined by the charge of the E2 glycoprotein. J Virol 89(15): 7536-49. doi: 10.1128/JVI.03645-14

Patabendige A and Abbott NJ (2014). Primary porcine brain microvessel endothelial cell isolation and culture. Curr Protoc Neurosci 69: 3.27.1-17. doi: 10.1002/0471142301.ns0327s69

Patabendige A. (2012). The value of in vitro blood-brain barrier models and their uses. ATLA 40:335-338. doi: 10.1177/026119291204000606

Patabendige A. (2012). Toward a humanised alternative to the use of laboratory animals for blood-brain barrier research. ATLA 40, PiLAS 1(1):12-13. doi: 10.1177/026119291204000515

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Fellowship

Status

Closed

Principal investigator

Dr Adjanie Patabendige

Institution

University of Liverpool

Grant reference number

NC/K500525/1

Award date

Sep 2012 - Mar 2016

Grant amount

£195,000