Unlocking Barriers to DNA Vaccine Immunogenicity: A Cross-Species Analysis of Cytosolic DNA Sensing in Skeletal Muscle Myocytes
Technical Report,10 Sep 2015,09 Sep 2016
Sir Mortimer B. Davis Jewish General Hospital Montreal H3T 1E2 Canada
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DNA vaccine technology holds great promise as a platform for developing vaccines against both emerging and established global pathogens. Despite this potential, significant challenges impede the capacity of DNA vaccines to prevent disease in humans. Foremost amongst these, is the gap between remarkable results obtained in pre-clinical mouse models and relatively modest immunogenicity observed in humans. The present work is testing the hypothesis that skeletal muscle myocytes sense cytosolic DNA and elaborate an inflammatory response to DNA vaccines and that species-specific differences in the cytosolic DNA sensing system bring about divergent inflammatory responses in human versus mouse skeletal muscle myocytes. We are pursuing the following specific aims 1 characterize the inflammatory response elaborated by myocytes following the delivery of DNA to the cytosol, 2 define the components of the cytosolic DNA sensing system that are present in skeletal muscle myocytes and 3 ascertain which components of the myocyte cytosolic DNA sensing system are engaged upon delivery of DNA to the cytosol. We are utilizing molecular, biochemical and proteomic methods to analyze the consequences of DNA vaccine vector delivery into mouse and human myocyte-derived cell lines and primary cells. We anticipate that our efforts will produce important insights on cytosolic DNA sensors and provide a key to unlock DNA vaccine immunogenicity for humans.
- Medicine and Medical Research