Conversion of Adenines to Inosines in RNA During Virus Infections Activates Innate Immune Responses

Abstract

Innate immune responses generated during viral infections are critical for protective anti‐viral immunity. The exact viral‐derived structures (also known as pathogen‐associated molecular patterns, PAMPs) that activate uninfected cells to induce activation signals are not completely characterized. To date, the viral PAMPs that are identified include dsRNA and 5′ triphosphate ssRNA, which are recognized by several cellular pathways such as SR‐A, PKR, RIG‐I, TLR‐3 and MAVS. During viral infections, the cellular enzyme ADAR‐1 (adenosine deaminase acting on RNA‐1) catalyzes conversion of adenines to inosines (A‐I editing), which is a pathway for blocking viral replication. ADAR‐1 activation in the infected cells leads to the presence of inosine‐containing viral and cellular RNA (Ino‐RNA). Here, we provide in vitro and in vivo data to affirm our hypothesis that the release of Ino‐RNA from infected cells and its interaction with surrounding uninfected cells is a potent stimulus for inflammatory innate immune responses. The innate response was confirmes by rapidly and potently induction of IFN‐b, TNF‐a, IL‐6 and RANTES. The A‐I editing increased secondary structures of RNA which resulted in activation of the dsRNA‐specific protein kinase (PKR). Our data uncover a novel strategy for uninfected host cells to detect viral infections in the surrounding tissue.