The role of Herpes simplex virus infection in neuropathology of Sanfilippo disease

About the Project

Title: The role of Herpes simplex virus infection in neuropathology of Sanfilippo disease

Synopsis: The aim of the project is to determine if HSV infection exacerbates neuropathological disease progression and hastens working memory defects in the mouse model of Sanfilippo disease, and whether IL1RA can mitigate this expected decline.

Details: Herpes Simplex Virus infections are typically benign, but in some rare cases, the virus translocates to the brain, where it leads to a rapid meningitis like infectious encephalitis disease, severe neurological damage and death in almost all cases.

Sanfilippo disease is a rare childhood dementia, caused by defects in the lysosomal enzyme SGSH. Lack of SGSH leads to accumulation of undegraded polysaccharide glycosaminoglycans and results in a progressive neurological decline in patients, characterised by severe neuroinflammation, hyperactivity, loss of working memory, motor decline and eventual death.

We have previously shown that neuropathology and loss of working memory in Sanfilippo disease are critically dependent on activation of the NLRP3 inflammasome, and indeed, delivery of IL1RA via gene therapy, which competes with IL1 for the IL1 receptor 1 on the surface of neurons, is able to completely block NLRP3 inflammasome activation and critically rescues the working memory defect in mice with the disease (Parker 2020). This has also led to a clinical trial in advanced stage patients with Sanfilippo using Anakinra (IL1RA), with some improvements in behaviour (Polgreen 2024), although cognitive improvements would not be expected by this stage. To follow up on this study we have also previously shown that the TLR3 viral mimetic PolyI:C, is also able to worsen chronic disease progression in the mouse model of Sanfilippo disease, showing behavioural exacerbation at high doses and neuronal dropout at low doses (Mandolfo 2024).

We have not shown, how a chronic active viral infection such as HSV might worsen the course of disease, but we have already set up a mouse model of HSV central and peripheral infection in Edinburgh for a different project with Prof Michael (liverpool). We would like to identify if HSV infection, either peripherally or centrally, exacerbates chronic neurodegenerative disease progression in Sanfilippo and using RNAseq, study the genes that are upregulated in neurons and microglia as a result of this infection, as well as comparative neuropathology, markers of inflammation (ILB4, GFAP), lysosomal storage(LAMP2) and NLRP3 activation (NLRP3, ASC, Caspase 1 activity). Finally, we will evaluate if IL1RA or other anti-inflammatory/anti-inflammasome genes delivered by gene therapy are able to modulate disease progression.

Potential impact: This study could help to define the role of the inflammasome and innate immunity in chronic neurodegenerative disease progression, and determine the factors that HSV uses to worsen disease progression, both in its benign peripheral form and in its encephalitis form.

Training: The student will learn techniques including, RNASeq, bioinformatics analysis of large datasets, immunohistochemistry, inflammation assays, behavioural and gene delivery techniques in mice, virology techniques and production of lentiviral or AAV vectors.

There is a vibrant community of PhD students in the CRM, and the student will have access to the expertise not only of the Bigger lab, but also the surrounding groups with expertise in many of the skills needed to complete the project.

Recruitment: Candidates are sought with a 2.1 or first in a biochemical, biological or biomedical degree path, together with at least 6 months previous wetlab experience.

Apply: All applications must be submitted through the Future Medicine PhD fellowships website.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.

The fellowships are open to students who are eligible for home fees at Edinburgh - i.e. you must be a UK national, or have settled status, and have. been "ordinarily resident" in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.