Title: Modelling sub-clinical vCJD infection in the UK population
Funder: Department of Health and Social Care

Abstract: vCJD was first reported in the UK in 1996. Since then 177 deaths from probable or definite vCJD have occurred with three related to transfusion of contaminated blood. Susceptibility to vCJD is linked with methionine/valine polymorphism at codon 129 in the PRNP gene with all genotyped cases of clinical vCJD being found in 129MM individuals. Two asymptomatic cases of vCJD in 129MV individuals have been reported in which PrPSc was identified in the spleen but not the brain. Material from one spleen has now been shown to be infectious. Retrospective tonsil and appendix studies have shown evidence of the presence of PrPSc in all 129 codon genotypes and all birth cohorts from 1941 with a prevalence rate of 1 in 2000 indicating a high carrier status in the UK. It is unknown whether they represent primary or secondary infections1. In animal studies, prion disease pathogenesis can be influenced by a variety of factors including host genetics (codon 129 of the prion protein gene), age at infection, route of infection and immune status such as co-infections. We hypothesise that codon 129 genotype of PrP is not only linked to susceptibility but plays a role in the peripheral sequestering of disease. Furthermore, we hypothesise that movement of infection from the periphery to the CNS is influenced by a variety of factors. We aim to determine if age of the individual and route of infection influences disease pathogenesis and whether codon 129 genotype of PrP plays a role in the process. Additionally, we aim to determine whether immune insults such as viral or systemic co-infection can alter disease pathogenesis and/or onset of clinical disease. We will utilise transgenic mouse models expressing the three human codon 129 genotypes of PrP. Mice will be inoculated with vCJD via CNS or peripheral route at different ages and tissues collected at time points through disease incubation. We will ascertain whether PrPSc is present in the peripheral tissues of these mice at these time points and whether this differs between genotypes. This will be carried out using a combination of immunohistochemistry, biochemistry and infectivity studies where appropriate. A second study will use mice inoculated peripherally with vCJD and a co-infection (viral or systemic) introduced approximately 50% through disease incubation. Tissues will be collected at different time points and analysed as previously. This study will be carried out in collaboration with NCJDRSU. Both The Roslin Institute and NCJDSRU have over 20 years of experience in investigating and characterising vCJD using transgenic mouse models of disease. The applicants involved in this proposal have a wealth of experience in vCJD disease pathogenesis and in the modelling of vCJD in mice and have published extensively in this area. By identifying factors which may influence disease pathogenesis and the onset of clinical disease we will provide data which can be used to further inform and refine risk assessment models, particularly for potential secondary vCJD transmission. In turn, this will allow further development and review of existing and prospective risk reduction measures. In addition, the data from these studies will improve our understanding of vCJD pathogenesis; this may lead to quicker diagnosis thus preventing sub-clinical human-to-human transmission.

Lay abstract: This proposal aims to address concerns regarding transmission of variant Creutzfeldt-Jakob disease (vCJD) a fatal disease affecting the brain and nervous system. We will determine if there is an association between a particular gene (the prion protein gene) and both age at and route of infection and whether this can change disease progression. In addition, we will investigate whether a co-infection, such as a viral or systemic infection, can influence how vCJD spreads through the body or affect the onset of clinical symptoms. At present there are no treatments or cures for vCJD and recent studies have shown there may be carriers of disease in the UK population that show no clinical symptoms but have the potential to infect other individuals. By investigating the influence of different factors on the spread of disease in the body and onset of clinical symptoms we can use the information to further develop risk assessments and risk reduction measures. We can also use the information to develop treatments. The work in this proposal will be carried out at The Roslin Institute. We will use mice that have been genetically modified to have the same prion protein related gene as humans. We will infect these mice via different routes and at different ages with vCJD. We will infect mice with vCJD and either a viral or systemic infection. We will study tissues taken from the mice at different time points throughout disease to establish whether vCJD can be detected and whether age at infection, route of infection or presence of another infection can affect disease progression. The Roslin Institute and NCJDRSU have over 20 years of experience in investigating and characterising vCJD using experimental mice. Both research centres have a wealth of experience in vCJD disease pathogenesis and in the modelling of vCJD in mice and have completed a number of successful studies in this area.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL