Innate virus recognition and autophagy
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 previous studies, 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.
In a recent study, we demonstrated that monocytes from older humans (age above 65) have impaired capacity to produce antiviral cytokines, type I intereferons (IFNs). Yet, the monocytes from older humans are still capable of inducing inflammasome activation and secreting inflammatory cytokines. We used a mouse model to mimic this condition – by deleting genes that promote IFNs, while leaving inflammasomes intact. Such mice succumbed to influenza virus infection. However, deleting caspase-1 or inhibiting IL-1beta resulted in improved recovery from flu infection. Notably, mice in both conditions had high titers of virus replication in the lung. These results suggest that caspase-1 dependent inflammatory responses kill mice after influenza virus infection. We wish to utilize this understanding to devise a better treatment strategy for older humans suffering from flu-related diseases.