Date:
May 7, 2014
Time:
Wednesday 7 May at 1 pm
Location:
Lower Atrium Meeting Room, Telethon Kids Institute, 100 Roberts Road, Subiaco
Contact:
Please RSVP parveen.fathima@telethonkids.org.au for catering purposes and to ensure adequate seating.
Genetic and functional studies of leishmaniasis: understanding the role of HLA
Presented by Jenefer Blackwell
Winthrop Professor, University of Western Australia
Senior Principal Investigator, Telethon Kids Institute
Affiliated Principal Investigator, Cambridge Institute for Medical Research
Abstract
The importance of host genetic factors in human susceptibility to visceral leishmaniasis (VL) is indicated by familial clustering and high sibling risk ratios. We recently reported (Nature Genetics, 2013, 45, 208-213) the first genome-wide association study of VL across major foci of disease caused by L. donovani in India and L. infantum chagasi in Brazil. The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations (Pcombined=2.76x10-17, OR 1.41, 95%CI 1.30-1.52), crossing the epidemiological divides of geography and parasite species. Haplotype analyses showed that the protective allele perfectly correlated with haplotypes carrying the DRB1*15, *16, and *01 allele groups, while increased risk was associated with the DRB1*13, *14, and *11 allele groups. Thus, the most important genetic risk factor for VL lies at the heart of eliciting T cell immunity. Reporter gene assays are being employed to determine whether the associations are due to regulatory polymorphisms that affect class II gene expression. A combination of in silico and experimental analyses are underway to determine how functional differences at the amino acid level directly influence epitope selection and antigen presentation driven by Class II DRB1 molecules. Our aim is to identify parasite epitopes that bind to specific DRB1 risk versus protective alleles, and to use this knowledge to design novel vaccines that can subvert the response to natural infection in susceptible individuals by prior exposure to antigenic epitopes that will bias the immune response towards protection.
All are welcome to attend. Nibbles will be provided.