Garcia-Blanco, Mariano A.
Professor, Microbiology, Immunology, and Cancer Biology
RNA-protein interactions in antiviral immunity and autoimmune diseases.
Ongoing work in my laboratory focuses on the role of an alternative splicing factor, the RNA helicase DDX39B, known to immunologists as BAT1, on immunity and autoimmunity. The connection to autoimmunity derived from work with Dr. Simon Gregory (Duke University): we showed that alternative splicing of the interleukin 7 receptor (IL7R) transcripts regulates levels of soluble IL7R and confers increased risk for multiple sclerosis, an autoimmune disorder of the central nervous system. We discovered the master regulator of IL7R splicing is the DExD/H RNA helicase, DDX39B, and showed that it is a multiple sclerosis risk factor [Galarza-Muñoz et al., 2017]. We also provided a molecular explanation for how genetic variation in IL7R exon 6 leads to silencing of this exon and a model for how DDX39B activates it [Schott et al., 2021]. Recently, we have shown that DDX39B controls important posttranscriptional regulatory networks in T regulatory cells and is required for expression of FOXP3, the master transcription factor in T-regulatory cells [Hirano, Galarza-Muñoz et al., in revision for eLife]. The work on IL7R has led to three US Patents 8,158,344, 10,961,581, 11,118,186 and the formation of Autoimmunity BioSolutions, which is commercializing novel therapies that target soluble IL7R to treat autoimmune diseases and cancer.
The second broad area of investigation in the laboratory focuses on RNA–protein interactions that impact infections caused by pathogenic RNA viruses. Our work on flaviviruses has identified human and mosquito pro- and anti-viral host factors, many of which are RNA binding proteins (RBPs) [Sessions et al., 2009]. The information gained from these studies has provided important mechanistic insights into how dengue, yellow fever, and Zika viruses replicate and how they evade immune defenses. This work has led to important insights on the role of post-transcriptional regulation on immune dysregulation by viruses and on the regulation of innate immunity by alternative splicing factors [Liao et al., 2021].