The innate immune system has evolved to recognize invading pathogens through pattern recognition receptors (PRRs). Because viruses are synthesized by the host cell machinery, the nature of viral signatures recognized by PRRs was unclear. Our research revealed that viral nucleic acids from dsDNA and ssRNA viruses serve as a viral signature, and that they are recognized by endosomal Toll-like receptors (TLR)-9 and TLR-7, respectively in plasmacytoid dendritic cells (pDCs).
Further, we demonstrated that in vivo, pDCs are required to secrete type I IFNs in response to genital herpes infection and mediate innate protection of the host. More recently, we discovered the role of autophagy in innate viral recognition. We demonstrated that TLR-7-mediated recognition of certain ssRNA viruses requires transport of cytosolic viral replication intermediates into the endosome by the process of autophagy in pDCs. This study demonstrated a link between innate viral recognition and autophagy. Unlike the pDCs, most other cell types recognize virus infection via the RIG-I-like receptors (RLRs) within the cytosol.
In a recent study, we demonstrated that autophagy regulates RLR pathway by removal of damaged mitochondria. In the absence of autophagy, reactive oxygen species (ROS) accumulate within the mitochondria, and turn off regulation of RLR signaling. Thus, autophagy is essential in 1) delivering viral ligands to endosomal TLRs, and 2) clearing damaged mitochondria and ROS, thus regulating RLR signaling. We are currently investigating the mechanism by which ROS regulates RLR signaling.