Host Determinants Associated with Susceptibility to Respiratory Syncytial Virus (RSV) Infection

Lower respiratory tract infections are the most frequent cause of mortality in low-income countries, in particular in newborns and in young children. Respiratory syncytial virus (RSV) which is the most important respiratory pathogen in this age group, causes a broad spectrum of respiratory symptoms from common cold to pneumonia and, typically, bronchiolitis. It is also associated with the development of asthma. RSV is a negative strand RNA virus that belongs to the family of Paramyxoviruses and is related to Measles, Mumps, Parainfluenza and Rubella virus. There are very limited prevention and treatment options at the moment, and clinical care is thus mainly supportive. Increasing evidence suggests that inherited genetic polymorphisms in the host genome affect susceptibility and severity in many infectious diseases, more than in any other types of diseases. However, only very few infectious disease-associated genetic polymorphisms are known, and those that have been identified so far in genome-wide-association studies (GWAS) only account for a small portion of heritability.

Aims;
The objective of this study is to identify functionally characterized genetic biomarkers and genetically validated potential drug targets for RSV using a new approach that combines a genomic in vitro screen with a clinical genetic association study. The specific aims of this project are

To identify cellular host factors that affect RSV infection by RNA interference using a green fluorescent protein (GFP)-expressing RSV mutant in a high-throughput genomic in vitro screen.
To identify known, disease-associated single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) of >0.05 in these host factor genes that affect RSV replication by database (NHGRI) search (www.genome.gov/gwastudies/)
To test if any of these SNPs that affect RSV replication correlate with the severity of RSV infection by genotyping samples from RSV-infected individuals using low density SNP arrays and quantitative polymerase chain reaction (qPCR). The samples will be provided from the NHS Lothian Bioresource which contains >90.000 respiratory specimen tested for a range (>10) of respiratory viruses including RSV (ethics approval provided).
To correlate demographic and disease-related parameters such as pneumonic consolidation in x-ray imaging, RSV PCR, WBC, CRP, comorbitities, treatment, length of hospitalization, disease burden (DALY) etc. with the patient genotype.
The advantage of this approach is the identification of functionally validated SNPs, in contrast to the vast majority of disease-associated SNPs (>14.000) that has been identified in other (mainly GWAS) studies whose function is completely unknown. Thus, this study is not only highly relevant and has strong translational impact, but also provides a proof-of-principle. From previous studies using a different virus we have preliminary evidence that the approach is feasible. The project is expected to have significant impact on clinical management and therapy of RSV-infected children and adults.