Extracellular dsRNA: Its Function and Mechanism of Cellular Uptake

Double-stranded RNA (dsRNA) is arguably the most potent viral trigger of innate immune signaling. Its activity has been recognized for over 5 decades, first as a toxin, then as a central component of the interferon system, as an efficient activator of antiviral responses and an immunomodulator for therapeutic applications. Nucleic acid sensing is the main basis for antiviral defense systems throughout the diverse forms of life from bacteria to plants and animals. Pattern recognition receptors of the host defense system not only sense viral dsRNA as a pathogen-associated molecular pattern in infected cells, but also recognize circulating endogenous dsRNA, a nonmicrobial signal, as a danger-associated molecular pattern, often leading to autoimmunity. Despite the effects of extracellular viral and host dsRNA associated with infection and autoimmunity, respectively, the understanding of cellular mechanisms for its recognition and uptake has only been appreciated in recent years. This review presents an overview of this unique form of nucleic acid, addressing its roles in infection, autoimmunity, and host sensing mechanisms. The goal of this review is to highlight the novel findings with a focus on extracellular recognition and uptake by the cell.