Plasmacytoid dendritic cell recognition of different classes of viruses by Toll-like receptors

Plasmacytoid dendritic cells (pDCs) were first identified based on their capacity to produce high levels of type I interferons in response to stimulation with viruses. Because of this striking effector function, it was hypothesized that these cells could play a role in the innate immune response against viruses. The Toll-like receptor recognition pathway had been well studied for the detection of many microbes of bacterial origin, yet the very nature of viruses created special challenges in identifying how they could be recognized by the TLRs; namely, how could a virus, synthesized using host cellular machinery, be distinguished from the host? Based on the ability of pDCs to produce robust levels of type I interferons in response to multiple viruses, we hypothesized that the role of these cells in innate immunity could be in sensing the presence of viruses.; We first investigated the molecular mechanisms of virus recognition by pDCs. Viruses represent a large group of pathogens with a broad range of invasion strategies, although most simply they can be categorized based on nucleic acid composition. We found that TLR9 recognizes the genomic DNA of dsDNA viruses, while TLR7 recognizes negative sense, ssRNA viruses based on the presence of RNA within endosomes. Therefore, our work contributed to the understanding that pDCs utilize exclusively intracellular TLRs to recognize viruses and thereby distinguish viral nucleic acids from self. Further examination of the requirements for intracellular replication intermediates in recognition of viruses by pDCs revealed that autophagy is involved in the recognition of ssRNA viruses through recognition of cytoplasmic replication intermediates. Finally, the role of pDCs during an in vivo mucosal viral infection was investigated using intravaginal infection with HSV-2. We found that pDCs play a pivotal role in early innate immune responses to genital HSV-2 infection. Specifically, pDCs were required for robust IFNalpha production at the local site of infection, and depletion of pDCs resulted in a marked increase in vaginal pathology and uncontrolled HSV-2 replication at the infection site. Such contributions to the understanding of how pDCs recognize viruses and subsequently act to assist in clearing these pathogens are critical to developing better treatments and vaccines against viral infections.