Sequencing; Transcriptomics; Human genome; Infectious diseases; Genomics; Host-pathogen interactions
Fellay Jacques (2016), Familial segregation of group B streptococcal infection in a consanguineous kindred., in Int J Infect Dis
, 51, 22.
Fellay Jacques (2016), Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis., in Front Immunol.
, 7(357), n/a.
Fellay Jacques (2015), The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals., in J Infect Dis
, 212(4), 578.
Hammer C., Begemann M., McLaren P.J., Bartha I., Michel A., Klose B., Schmitt C., Waterboer T., Pawlita M., Schulz T.F., Ehrenreich H., Fellay J. (2015), Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses, in American Journal of Human Genetics
, 97(5), 738-743.
McLaren P.J., Coulonges C., Bartha I., Lenz T.L., Deutsch A.J., Bashirova A., Buchbinder S., Carrington M.N., Cossarizza A., Dalmau J., De Luca A., Goedert J.J., Gurdasani D., Haas D.W., Herbeck J.T., Johnson E.O., Kirk G.D., Lambotte O., Luo M., Mallal S., Van Manen D., Martinez-Picado J., Meyer L., Miro J.M., Mullins J.I. (2015), Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load, in Proceedings of the National Academy of Sciences of the United States of America
, 112(47), 14658-14663.
Susceptibility or resistance to infection is the final result of dynamic interactions between host, pathogen and environment. In clinically relevant viral diseases, the genetic constitutions of both the infected patient and the invading virus are essential determinants of symptoms and outcome. Because it is now feasible to scan entire genomes in an unbiased manner, the respective and combined impact of host and pathogen genetic diversity on viral diseases can be comprehensively assessed.The first 4 years of SNSF Professorship support allowed my group to start an in-depth exploration of the influence of human genomic variation on viral respiratory infections in children, using an “extreme phenotype” study design. We recruited previously healthy patients, admitted to a pediatric intensive care unit following infections by common respiratory viruses (e.g. respiratory syncytial virus, rhinovirus or influenza virus), and searched for deleterious variants in exome and RNA sequencing data. The project served as a catalyst for the creation of an efficient sequencing pipeline and the development of novel bioinformatic methods for DNA and RNA analysis. In addition, in an exciting demonstration of the potential of the proposed approach, we recently identified rare deleterious mutations in genes involved in intra-cytoplasmic recognition of viral nucleic acids, which could explain the exceptional disease severity in some study subjects. I here propose to build on our promising results and to take advantage of the increased throughput and dropping cost of sequencing to further develop host and viral genomic analyses. My plan is to complete the human genomic analysis of viral respiratory infections, to run in-depth analyses of the viral genomes, and to broaden the scope of the study by including extreme phenotypes caused by two additional viruses of major public health importance: hepatitis B virus (HBV), and human immunodeficiency virus (HIV), which has already been the focus of much attention in my group. All putatively causal variants identified in the different genome-wide scans will then be validated and functionally characterized to confirm their biological impact and assess their clinical relevance.The systematic study of human and viral genetic diversity represents a new frontier in the exploration of phenotypic variation. It has the potential to improve our understanding of host-pathogen interactions and of disease pathogenesis. Consequently, the findings of this program could help develop novel diagnostic tools, preventive strategies and therapeutic interventions, and contribute to the growth of personalized medicine in infectious diseases.