023-23 – Investigating direct and indirect effects of viral infections on the brain and prevention via immune suppression.

Viral infections are known to cause severe neurological complications, but their mechanism of CNS involvement is less established but highly desirable to inform on potential new treatment options. It is postulated that viruses can directly infect the CNS through blood-brain barrier (BBB) damage, or indirectly by exerting excessive host immune response. Herpes Simplex Virus type 1 (HSV-1) causes neuronal death and is the most common cause of herpes simplex encephalitis. Varicella Zoster Virus (VZV) is commonly known to cause chickenpox and later reactivation can causes shingles. Vasculopathy caused by VZV is linked to VZV encephalitis and in conjunction cause the exacerbation of further complications such as stroke and seizures. My project aims to use microfluidic chips to develop a novel “brain-on-a-chip” co-culture model of endothelial cells, astrocytes, microglia, and neurons, rather than the using a traditional animal model. These chips have the benefit of using host specific cells that can express host specific genes and receptors providing insight that animal models can’t do alone and allows strikingly similar BBB recreations. Using syringe pumps allows the introduction of shear stress comparable with that found in vivo, which is not possible with other in vitro models like Transwell®. Electrodes can also be placed either side of the endothelial monolayer and TEER measurements can be taken. I aim to find the key factors of BBB damage and neuronal death (VZV compared to HSV-1). I’m able to conduct fixed staining and real-time visualise infection, which will be very beneficial for observing these processes. Clinical studies conducted by my group have identified cytokines/chemokines and brain-injury proteins of interest. I will measure these in the model and block pathways to study whether we can prevent detrimental effects on brain cells. This will increase our understanding of viral disease mechanisms and possible targets for the development of new therapeutics.