Understanding innate immune pathway modulation using nanoparticles

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The innate immune system is the fast acting, first arm of immunity. Components of the innate immune system are able to sense possible pathogenic threats and take action to limit their deleterious effects, as well as send out signals to alert other cells in the body. This is accomplished through cellular recognition of pathogen-associated molecular patterns, red flags to alert the cell of a potential infection. One group of molecules that can indicate an infection are nucleic acids, including double-stranded RNA and single-stranded RNA or DNA with specific motifs or found in an unusual cellular compartment. Once activated, the immune response induced by recognition of nucleic acids is mediated by signaling molecules such as type I interferon or pro-inflammatory cytokines; in addition, this innate response informs the adaptive immune response. Nanoparticles are an excellent tool to further our understanding of fundamental innate immune mechanisms in healthy cells. Nanoparticles can be loaded with large amounts of a nucleic acid, creating concentrated "bombs" to be delivered to the cells. In some cases, this leads to an enhanced immune response within the cells. The long-term central goal of this research program is to understand cellular immune responses to nanoparticles loaded with nucleic acids. This will be achieved by addressing two overarching research questions: why is there variation in this response? And what can this teach us about fundamental mechanisms behind innate immune pathways? Overall, this proposal will provide the foundation for my novel research program. This research will contribute to advancing our fundamental understanding of innate immune pathways in healthy cells. To this end, nanoparticles will be used as a tool to help further tease apart the intricacies of cellular immune responses, from detecting to responding to nucleic acids. Using nanoparticles that amplify the stimulating power of nucleic acids gives us a novel avenue for elucidating the complex and intricate signalling cascades involved in immune-recognition. The data produced by this research program are valuable to the natural sciences, and will support further research into innate immunity. The highly conserved nature of the innate immune system will allow for information gleaned in human models to be applied to other species and to broaden our understanding of the immune system of all animals.