Ashish Dhir Research Group
Nucleic acid metabolism and innate immunity
Research in a Nutshell
Innate immunity is the first line of defence against viruses a feature inherent to every cell in our body. This ancient and fundamental mechanism for detecting viral infection employ sensors that recognize viral nucleic acids (DNA & RNA). Sensor-nucleic acid recognition triggers a very potent antiviral response by activating the production of type I interferons (IFNs), a powerful cytokine that restricts the viral spread and results in clearance of infected cells.
Nucleic acid recognition is the key strategy of viral detection, yet its very nature raises fundamental questions of self vs non-self discrimination because of the abundance of self-derived nucleic acids in all cells. In fact, inside a human cell, the nucleus and the mitochondria (relics of an ancient bacterium) represent two double-membraned compartments that act as a major source of host nucleic acids. DNA as a genetic material is transcribed into RNA, an intermediary molecule essential for protein production. RNA synthesis is a stochastic step that generates a lot more than what is required by the cell. Whilst majority of the 3 billion bases of the nuclear genome are transcribed into RNA only ~2% encode for proteins. Mitochondria, on the other hand, comprise a compact closed circular DNA genome of around ~16 thousand bases, which is extensively transcribed in both the directions – yet generates considerable waste as transcribed RNA from one of the two strands is mainly non-coding (encoding a single protein).
Importantly, the majority of the ‘waste’ non-coding RNA of nuclear and mitochondrial origin is rapidly degraded by RNA nucleases, often in cooperation with RNA helicases. Such RNA degradation is central to homeostasis, since aberrant RNA accumulation can perturb normal cellular functions - either by sequestration of RNA binding proteins, or by promoting ‘aberrant’ nucleic acid structures such as RNA-DNA hybrids or duplex RNAs. A potential consequence is that these structures may be misrepresented as a ‘foreign’, inducing an immune response against self.
We are interested in identifying cellular pathways that restrict the accumulation and/or mislocalization of potentially harmful RNA intermediaries of self-origin. In doing so, I envisage the discovery of new pathways involved in nucleic acid metabolism, a better understanding of cellular homeostasis, and novel insights into autoimmunity caused by excessive activation of nucleic acid sensors.
University of Edinburgh Chancellor's Fellowship
RNA, Innate Immunity, Mitochondrial Disease, Autoimmunity