Mammalian Toll-like receptors (TLRs) play a critical role in detection of invading pathogens as well as triggering of subsequent inflammatory and immune responses. Dr. Shizuo Akira's research has been instrumental in shaping our understanding of innate recognition by these receptors. Amongst the many major discoveries from his laboratory, his research has uncovered the role of TLR4 in the recognition of LPS; identified differential signaling by TLRs though selective use of adaptor proteins, such as MyD88 and TRIF; and described the ability of TLR9 to recognize bacterial DNA containing unmethylated CpG dinucleotides (pathogen-derived DNA) and TLR7 to recognize a derivative of imidazoquinoline, an antiviral chemical compound that is now used for treatment of genital warts caused by papilloma virus as well as single-stranded RNA of viruses, including influenza virus.

Furthermore, he recently demonstrated the role of two DExD/H box RNA helicases --- retinoic acid inducible protein-I (RIG-I) and melanoma differentiation-associated gene 5 (mda-5) --- in anti-viral responses by recognizing RNA in the cytoplasm in a TLR independent manner. Research from Dr. Akira's laboratory continues to be at the forefront of studies on recognition pathways for the induction of innate and adaptive immunity. Don't miss the opportunity to hear from this remarkable scientist.

Dr. Akira has been studying the role of Toll-like receptors (TLRs) and their signaling pathways mainly by gene targeting. He studied the molecular mechanisms of immunoglobulin gene rearrangement as a graduate student at Osaka University and for two years as a postdoctoral fellow at the University of California at Berkeley with Hitoshi Sakano. After returning to Japan, he studied IL-6 gene regulation and IL-6 signaling pathways in the laboratory of Tadamitsu Kishimoto, who discovered interleukin-6. Among his contributions, he cloned two important transcription factors involved in IL-6 signaling, NF-IL6 (also called C/EBP beta) and STAT3. In 1996, Dr. Akira left Dr. Kishimoto’s lab to become a professor of biochemistry at Hyogo College of Medicine. At that time he made the seminal observation that mice lacking the adaptor protein MyD88 were unresponsive to lipopolysaccharide (LPS), a major immunostimulatory component in the cell wall of Gram-negative bacteria, indicating that the LPS receptor uses MyD88 for signaling. MyD88 harbors a domain homologous to the cytoplasmic portion of IL-1 receptors and TLR family members. Therefore, he hypothesized that a member of the Toll-like receptor family was a candidate LPS receptor, and began making mice deficient in each of all members of the of TLR family. Together with Dr. Bruce Beutler’s findings with LPS unresponsive natural mutant mice, Dr. Akira demonstrated that TLR4 is essential for LPS responsiveness.

Dr. Akira went on to identify ligands of other TLR members using the TLR-deficient mice he had generated. In particular, he made the seminal discovery that bacterial DNA containing unmethylated CpG dinucleotides (pathogen-derived DNA) signaled via TLR9. Furthermore, he demonstrated that TLR7 recognizes a derivative of imidazoquinoline, an antiviral chemical compound that is now used for treatment of genital warts caused by papilloma virus as well as single-stranded RNA of viruses, including influenza virus.

Dr. Akira has subsequently been at the forefront of research that has resulted in major discoveries of TLR signaling and function. These include his demonstration for the first time that the signaling pathways by which individual TLRs signal differ from one another, thereby resulting in different gene expression and biological responses. Furthermore, he showed that the difference in signaling pathways among TLRs is due to selective usage of adaptor molecules, such as MyD88 and TRIF. Finally, he recently demonstrated that pathogen-derived DNA and RNA can be recognized in the cytoplasm in a TLR-independent manner, by signaling through RNA-helicases.

More information available at
http://www.jst.go.jp/erato/project/asm_P/asm_P.html

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