Grant: Operating Grant

Double stranded RNA (dsRNA) is a common form of nucleic acid found in virus-infected cells, but not in healthy cells. Virus infection often causes cells to die, releasing dsRNA into the extracellular space. It has been known for many years that extracellular dsRNA acts as a "viral toxin", causing many of the symptoms associated with "the flu". Of no surprise, dsRNA is a potent activator of the innate immune response and causes the rapid induction of the cytokine interferon. Although cells have many proteins that recognize and bind dsRNA once it is within cells, for many years it was unknown how cells recognize dsRNA outside of cells. We recently found that class A scavenger receptors (SR-As) are critical for the production of interferon in response to extracellular dsRNA. However, it is unknown how SR-As function in this role. Furthermore, it is unclear how dsRNA brought in by SR-As reaches the cytoplasm, where many dsRNA-binding proteins are found, as SR-As bring dsRNA into cellular vesicles via endocytosis. Once in the cytoplasm, a protein called IRF3 is critical for making interferon. Since it plays such an important role, most viruses have evolved ways to degrade or inactivate IRF3. We recently found that IRF9 can make interferon in response to dsRNA in the absence of IRF3. This is a new role for IRF9, thus nothing is known how IRF9 is working. In this grant, we propose experiments to understand in detail the events that allow extracellular dsRNA to make interferon. Extracellular dsRNA not only causes clinical symptoms of virus infection, it also plays an important role in autoimmunity. In addition, synthetic dsRNA is being tested in clinical trials as an adjuvant. Thus, understanding how host cells recognize and respond to dsRNA is of wide clinical importance, particularly for the development of effective therapies against severe virus complications and autoimmune diseases.