Innate immunity is the first line of defense against microbial pathogens, including viruses. These mammalian host cells have evolved unique strategies to sense viral infection by recognizing a variety of viral components.

“We have been studying TLR since the early stages of this emerging research field.”

Members of Toll-like receptors (TLR), including TLR3, TLR7, and TLR9, are localized in the endosomes where they detect virus-derived nucleic acids such as double-stranded (dsRNA) and single-stranded RNA (ssRNA) and DNA, respectively. In the cytoplasm, RIG-I-like RNA helicases (RLH), including RIG-I and Mda5, participate in the detection of triphosphate ssRNA and double-stranded RNA.

In spite of their distinct downstream signaling pathways, they result in the release of type I interferon and other pro-inflammatory cytokines to establish successful antiviral immunity. Our group has made a great contribution to the dissection of these pathways. This brief review gives an updated overview of the signal pathways via TLRs and RLHs, which may help readers to understand the importance of these pathways in the sensing of viral infections as well as in the control of antiviral innate immune responses.

We have been studying TLR since the early stages of this emerging research field. We were the first group to show that MyD88—initially identified as an adaptor for IL-1R signaling—deficient mice are unresponsive to bacterial lipopolysaccharide (LPS). Soon after the discovery that TLR4 is a receptor for LPS, we found that MyD88 is an intracellular adaptor molecule essential for the TLR family members.

Since then, we have been exploring how TLRs detect pathogen components and how they signal for effective and appropriate immune responses against pathogens. We have recently found TLR-independent pathways for the detection of viral nucleic acids in the cytoplasm, and are currently analyzing their roles in antiviral immunity.

A host has multiple defensive mechanisms that can eliminate viruses by recognizing viral nucleic acids in different intracellular compartments. Conversely, viruses have developed immune evasion mechanisms specifically counteracting these pathways. For example, the NS3/4A serine protease complex of HCV inhibits RLH-signaling pathways by targeting IPS-1, an adaptor for RLH. Therefore, the manipulation of TLR- and RLH-pathways has therapeutic potential in the fight against infectious diseases caused by viruses.