Tuberculosis is a major public health problem. One-third of the population of the world is estimated to be infected with Mycobacterium tuberculosis (Mtb), the etiological agent causing tuberculosis (TB), and active disease kills nearly 2 million individuals worldwide every year. Successions of treatments of TB have quickly become ineffective as the agent rapidly becomes resistant. However, strikingly, only 10% of infected individuals develop the disease. In other words, while Mtb quickly develops resistance to new drugs, roughly 90% of individuals are naturally resistant to infection (when not co-infected by agents, which compromise the immune system, such as HIV). Several lines of evidence indicate that genetic factors contribute to inter-individual differences in susceptibility to TB, including the observation that monozygotic twins have considerably higher concordance rates for tuberculosis morbidity than do dizygotic twins. In addition, multiple rare single-gene mutations with high penetrance have also been linked with susceptibility to mycobacteria. However, although genetic studies of TB have identified important pathways involved in protective immunity, very little is known about the underlying genetic determinants or mechanisms contributing for differences in susceptibility at the population level. Here, we propose to use a combination of empirical and statistical approaches to identify genes and regulatory pathways that contribute to inter-individual and inter-population variability in the immune response to Mycobacterium tuberculosis infection. Specifically, we will study inter- individual variation in the immune transcriptional response of dendritic cells following infection with Mtb, and map the genetic loci that are associated with such variation (eQTLs). To our knowledge, this will be the first genome-wide study of variation in molecular quantitative traits and associated genetic markers that underlie inter-individual variation in immune response to infection with Mtb, and ultimately variation in susceptibility to TB.
The goal of this study is to identify genes and entire pathways whose regulatory response to infection with Mycobacterium tuberculosis underlies inter-individual variation in susceptibility to Tuberculosis.
|Kariuki, Silvia N; Blischak, John D; Nakagome, Shigeki et al. (2016) Patterns of Transcriptional Response to 1,25-Dihydroxyvitamin D3 and Bacterial Lipopolysaccharide in Primary Human Monocytes. G3 (Bethesda) 6:1345-55|
|Blischak, John D; Davenport, Emily R; Wilson, Greg (2016) A Quick Introduction to Version Control with Git and GitHub. PLoS Comput Biol 12:e1004668|
|Pacis, Alain; Tailleux, Ludovic; Morin, Alexander M et al. (2015) Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 25:1801-11|
|Blischak, John D; Tailleux, Ludovic; Mitrano, Amy et al. (2015) Mycobacterial infection induces a specific human innate immune response. Sci Rep 5:16882|
|Ã‡alÄ±ÅŸkan, Minal; Pritchard, Jonathan K; Ober, Carole et al. (2014) The effect of freeze-thaw cycles on gene expression levels in lymphoblastoid cell lines. PLoS One 9:e107166|
|Siddle, Katherine J; Deschamps, Matthieu; Tailleux, Ludovic et al. (2014) A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection. Genome Res 24:850-9|
|Barreiro, Luis B; Tailleux, Ludovic; Pai, Athma A et al. (2012) Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A 109:1204-9|