Within the Infection Neuroscience Lab we have a number of cross-cutting research projects that sit within the following areas:
- Blood-Brain Barrier Model
- Murine Model
- Clinical Biomarkers
- Neuroimaging
- Neuro-Cognitive Sequelae
- Outcome Measure and Prediction
Dr Claire Hetherington
Postgraduate Research Associate
Blood-Brain Barrier model
In my postdoctoral research I am investigating the critical connection between COVID-19 infection, the body’s immune response, and damage to the brain. When someone gets infected with COVID-19, their body's immune response is triggered, causing various cells to release signalling molecules called cytokines. The cells that line blood vessels lay a crucial role in maintaining the blood-brain barrier, which is a protective barrier that keeps harmful substances out of the brain. However, when exposed to COVID-19 and cytokines produced by immune cells, endothelial cells can become activated and start producing even more inflammatory cytokines that enter the brain. This, in turn, leads to activation of microglia and astrocytes, which are special cells in the brain responsible for immune responses and supporting neuronal function. However, when these cells are excessively activated due to the cytokine signals, it can result in damage to neurons and, in severe cases, even neuronal death.
To study this, we can grow all these types of cells in the laboratory, find which molecules are produced in response to virus exposure and see how the different types of cells respond to them. This is called “in vitro modelling” as we are modelling what happens in the brain. By doing so, we can determine the pathway of events that lead to neuronal damage. By understanding this pathway, scientists can develop strategies to mitigate the neurological effects of the virus and potentially find new ways to protect the brain during such infections.
Ms Sarah Boardman
PhD Student
Blood-Brain Barrier Model
My PhD focuses on developing an in vitro co-culture blood-brain barrier (BBB) model using microfluidic chips. Microfluidic chips allow the spatial separation of different cell types; more similar to how these environments are biologically. This is important as each cell type can be cultured to their optimum conditions, which is likely to have biological relevance in an in vitro BBB model. As well as the ability to more accurately replicate how an infection would occur in vivo.
Using microfluidic chips, I aim to culture a 3D endothelial lumen in apical/outer chambers and use a syringe pump to accurately model a haemodynamically relevant shear flow environment. In the basolateral/inner chamber I will culture neural and glial cells (neurons, astrocytes, microglia), which are able to communicate physically and cellularly through micro porous gaps between chambers. Electrodes can be inserted into the microfluidic chip either side of the endothelial monolayer, which allows transendothelial electrical resistance (TEER) measurements to be quantified and used to determine barrier integrity. Imaging tight junction proteins to assess their level of expression in the endothelial cells will also convey the integrity of the barrier in the chip. Once a complete BBB model has been established, I will infect the endothelial chambers with two types of viruses, Herpes simplex virus-1 and Varicella zoster virus, and observe their effects on the model. To these infected BBB models, I intend to add neutrophils to observe their behaviour during viral infection which can be visualised in real-time. Finally, I will isolate potential targets for therapeutics that could be used to treat diseases caused by BBB damage (e.g., encephalitis). I will do this by inhibiting different chemoattractant proteins, that have previously been identified by The Infection Neuroscience Lab, to observe their ability to prevent BBB damage.
Dr Cordelia Dunai
Postgraduate Research Associate
Murine Model
We are studying mouse and hamster models of SARS-CoV-2 infection to further understand brain complications of COVID-19. We find that even in the absence of direct viral infection, there is immune activation in the brain and we aim to investigate how to prevent and treat brain complications from COVID-19 using this model.
Clinical Biomarkers
A lot of information can be gathered by measuring proteins in blood-- called biomarkers. Our study measured different types of biomarkers in participants' blood that relate to different health events. Participants who had neurological complications from COVID-19 were found to have higher levels of proteins that are released from damage to the nervous system and these are a useful, measurable biomarker for future therapeutic strategies.
Dr Franklyn Egbe Nkhongo
Postgraduate Research Associate
Clinical Biomarkers
My main research activity is assessing diagnostics and prognostics biomarkers of neurological insults and immunology/inflammatory mediators in COVID-19 and Encephalitis patients. We use ultra-sensitive bead-based digital multiplex immunoassay to quantify clinical biomarkers in patients' samples to inform on clinical outcomes, likely disease mechanistic, potential therapy targets and for prognostics purposes. The main objective is to better understand and manage neurological complications in COVID-19 and Encephalitis. We use the Quanterix SR-X simoa platform to quantify biomarkers of brain injury, neurofilament light (NF-L), total tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), phosphorylated Tau (p-Tau-181), Aβ40, and Aβ42 and the Bio-Plex Pro Human 48-Plex Cytokine Panel (Bio-Rad) to quantify 48 immunology biomarkers.
Dr Mark Ellul
NIHR Clinical Lecturer in Neurology
Clinical Biomarkers
I am a Clinical Lecturer (NIHR) in Neurology and a Specialist Registrar in Neurology at the Walton Centre in Liverpool. I work on autoimmune disorders of the central nervous system and central nervous system infections. In particular, I focus on improving the diagnosis of encephalitis, a devastating neurological condition characterised by inflammation of the brain.
Encephalitis is most often caused by either a viral infection of the brain (viral encephalitis), or the bodies own immune defences attacking the brain (autoimmune encephalitis). My work focuses on understanding the mechanisms by which viruses and the immune system can damage the brain, identifying targets for future therapies to improve patient outcome.
Understanding pathogenesis and outcome of encephalitis using multiomic analyses of cerebrospinal fluid (CSF) and blood
Through multicentre UK studies over several years we have recruited patients with encephalitis (both viral and autoimmune), mimicking conditions including delirium, toxic and metabolic disorders, and controls with headache disorders. Using samples from these patients we studied the CSF and blood, focusing on the proteome (using liquid chromatography-mass spectrometry), the metabolome (using 1H nuclear magnetic resonance spectroscopy) and the transcriptome (using gene expression microarray). These powerful datasets are combined with clinical data and imaging to illuminate pathogenic mechanisms in encephalitis, as well as to identify markers of aetiology and prognosis. Markers identified from these analyses of human samples provide hypotheses to test in murine models of encephalitis.
Understanding disease mechanisms of postinfectious autoimmunity in herpes simplex virus encephalitis
Herpes simplex virus (HSV) encephalitis, the most common cause of encephalitis in the UK, is a devastating central nervous system infection with high morbidity and mortality. Around a third of patients who recover from HSV encephalitis later experience an autoimmune relapse, sometimes associated with autoantibodies against the N-methyl-d-aspartate receptor (NMDAR) or against unknown targets. It is unclear why some patients develop autoimmune relapse and others do not, or whether corticosteroid treatment can avoid relapse. This study uses unique samples, with detailed clinical data, collected during a recent randomised controlled trial of adjunctive dexamethasone for HSV encephalitis (DexEnceph). We aim to investigate the mechanisms underpinning secondary autoimmunity in encephalitis, to understand the mechanisms by which the adaptive immune response contributes to the pathogenesis of HSV encephalitis. This study will pave the way for targeted immune therapy for HSV encephalitis, and has broad translational implications for other post-viral autoimmune conditions.
Intravenous Immunoglobulin in Autoimmune Encephalitis in Adults –A Randomised Double-Blind Placebo-Controlled Trial
The ENCEPH-IG trial is a study led by investigators from the University of Liverpool looking at whether or not early treatment with Intravenous Immunoglobulin improves recovery in autoimmune encephalitis. Autoimmune encephalitis is inflammation and swelling of the brain caused by the body’s own immune defence system. It affects about 1 in 100,000 people per year in the UK.
Autoimmune encephalitis is treated with steroids, which reduce inflammation and swelling. If patients are not improving, intravenous immunoglobulin (IVIG) is often also given, usually after a couple of weeks. The ENCEPH-IG trial is a study looking at whether or not early treatment with IVIG improves recovery. Read more about the ENCEPH-IG trial.
Dr Yun Huang
NIHR Academic Clinical Fellow
Clinical Biomarkers
There is emerging evidence of links between COVID-19 infections and immune-related brain and nerve injuries. These conditions include inflammation and demyelination of the central and peripheral nervous system. They can have significant impact on patient’s quality of life; however, we have little understanding of the biological processes underlying these conditions.
My project focuses on characterising the group of patients who developed immune-related brain and nerve injuries related to COVID-19. I aim to identify clinical risk factors to developing these immune-related complications. I will be analysing blood samples to identify possible biomarkers as well as mechanisms of immune dysregulation. I hope this research will benefit patients in a wide range of viral infection induced immune complications and identifying novel treatments that improve patient outcome in the long-term.
Dr Orla Hilton
Academic Foundation Doctor
Clinical Biomarkers
Stroke, defined as when a clot or a bleed reduces blood flow to certain areas of the brain, is a serious neurological complication of infection with COVID-19. Studies report between 1-2% of patients suffered from a stroke during the pandemic and on average these patients were younger compared to stroke patients who were not infected with the virus. In general, stroke in the young poses a great threat to socioeconomic stability, due to its often-disabling nature and sequelae. Thus, in my project I am seeking to understand the risk factors and outcomes of COVID-19-related stroke in younger people and to investigate any associated blood biomarkers in these patients.
Dr Ali Alam
Honorary Clinical Fellow
Neuroimaging
I am a medical trainee based in London. My research focuses are neurological infectious diseases and global health. I have worked on volumetric seizure prediction modelling in encephalitis. I am also interested in emerging zoonotic brain infections. My other research interest is in healthcare provision for displaced populations. In 2019, I worked in the Kutapalong refugee camp, researching gaps in healthcare provision for the forcibly displaced Myanmar nationals (Rohingya) population.
Ms Bethany Facer
PhD Student
Neuroimaging
My research interest is neuroimaging in disease populations. I am working on the DexEnceph study investigating imaging alterations in herpes simplex virus encephalitis and the associations with inflammatory markers. I am also a member of the neuroimaging working group for the COVID Clinical Neuroscience Study (COVID-CNS) where I coordinate and analyse the data. At present I am focusing on a population of people with SARS-CoV-2 induced movement disorders.
Mr Cory Hooper
PhD Student
Neuroimaging
My research focuses on the neuropsychological profiling and quantitative MRI analysis in patients with herpes simplex encephalitis. This work is performed in context of the DexEnceph UK national trial.
Dr Brendan Sargent
Honorary Clinical Fellow
Neuroimaging
I am an honorary clinical fellow with the University of Liverpool, and work with the COVID-CNS study to explore the effects of infectious diseases on the central nervous system and cognition. I am also a Clinical Research Fellow with the Autoimmune Psychosis Group at the Univeristy of Oxford. Here I support the SINAPPS2 and PPIP2 studies, which aim to establish the prevalence of antibody mediated psychosis, and whether immunological treatments might lead to better outcomes for these patients.
Dr Greta Wood
NIHR Academic Clinical Fellow
Neuro-Cognitive Sequelae
I am an NIHR Academic Clinical Fellow in Infectious Diseases working to understand how interacting biological, geographic and social factors impact TB mortality and transmission. I worked as the Clinical Research Fellow for the national COVID-19 Clinical Neuroscience Study, researching acute neurological and neuropsychiatric complications of COVID-19. I am currently studying the impact of COVID-19 on cognition, exploring clinical, biomarker and neuroimaging correlates. I am a member of the World Health Organisation Neurology and Public Health Global Forum and lead the WHO/UoL-funded Global Brain Health Clinical Exchange Platform. I work within the collaborating Global Neuro Research Coalition. My other research focuses are seizures in encephalitis and the aetiology of brain infection in low- and middle-income countries.
Dr Rajish Shil
NIHR Academic Clinical Fellow
Outcome measure and prediction
I am an NIHR Academic Clinical Fellow in Neurology, based in Liverpool. I am also a specialty trainee in Neurology, based at the Walton Centre of Neurosurgery and Neurology, NHS England. I graduated from RAK Medical and Health Sciences University, United Arab Emirates in 2015, completed ACGME-I accredited Internal Medicine residency, in Abu Dhabi, and qualified as a board-certified Internist. I am a collegiate member of the Royal College of Physicians, London, and currently an honorary clinical fellow at the University of Liverpool. I am currently working on the national COVID-19 clinical neurosciences study, with a brain infections group at the University of Liverpool. My research interests include brain infections, autoimmune encephalitis, demyelinating disorders, and movement disorders.
COVID-19 can affect the brain, nerves, and mind. It can lead to brain infection, stroke, and mental health illness among other problems. We don’t know how this happens in many cases. These effects can be long-lasting and can change over time. This study looks at people admitted to hospital with COVID-19-causing brain, nerve, or mental health illness. We are reviewing their case note data to assess if their personal background, pre-existing health conditions before COVID and the clinical features have a role in their illness and in their long-term recovery in the form of any difficulties in their activities of daily living and impact on the occupation post-recovery. We are comparing with people, who gets COVID-19 without it affecting their nervous system or mind. We are assessing for features that link to more severe illness and poorer outcomes. If so, this could help target those most at risk of a poor outcome and an appropriate treatment and support could be provided by the healthcare professionals.
Dr Arina Tamborska
Honorary Clinical Fellow
Outcome measure and prediction
I am a neurology resident and clinical researcher, currently based at the Harvard T. H. Chan School of Public Health as a Frank Knox fellow. I received MBChB with Honours with a joint Pharmacology BSc from the University of Edinburgh and have since pursued clinical academic training at King’s College London and the University of Liverpool. As an NIHR Academic Clinical Fellow with the Infection Neuroscience Lab and the Liverpool's Brain Infections Group, I was active in COVID-19 neurology research and led the UK surveillance for neurological events following vaccination. My research interests intersect neuroepidemiology, neurovascular disease and prevention of neurological disorders. Recently I secured Wellcome Trust PhD funding and I am currently preparing a project investigating vascular and infective contributions to dementia.
Dr Thomas Hughes
Academic Foundation Doctor
Outcome measure and prediction
The SEIZURE Score was published in 2022 by Wood et al. in order to stratify the risk of seizure in encephalitis patients from UK cohorts. I am following up on this study with an international validation project. Invitations have been sent out to members of the Global NeuroResearch Coalition and previous authors affiliated with the Infectious Neuroscience Lab. All interested groups have been asked to complete a data sheet for their encephalitis cohorts which will be run through the existing SEIZURE scoring systems; over 1500 patients are expected to be involved from 10-15 countries. This will enable us to determine the discriminatory ability of the scoring systems in different populations with varying demographic and aetiologies to that seen within the UK. From here we can determine countries for whom the current scoring system is a useful stratification tool and the countries that would benefit from the development of a local scoring tool unique to their own populations. The end-goal of this field of research is to stratify patients by risk to begin trialling the efficacy of primary anti-epileptic prophylaxis on encephalitis patients at high risk of seizing.
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