Research

Studies on innate immunity

The Project Leader's Profile

Shizuo Akira

Osaka University School of Medicine (1977)
Osaka University, Graduate School of Medicine (1984)

Research Fellow, University of California, Berkeley (1985-1987)
Research Associate (1987-1995), Associate Professor (1995), Institute for Molecular and Cellular Biology, Osaka University
Professor, Hyogo College of Medicine (1996-1999)
Professor, Research Institute for Microbial Diseases, Osaka University (1999-present)
Center Director, Osaka University Immunology Frontier Research Center (2007-present)  

2001 Hideyo Noguchi Prize, 2002 Osaka Science Prize, 2003 Takeda Medical Prize, 2004 Prize of Pricess Takamatsu Cancer Reseach Fund, 2004 Robert Koch Prize, 2005 The Emperor's Purple Ribbon Medal, 2006 Asahi Prize, 2006 William B Coley Award, 2007 Uehara Prize, 2007 The Japan Academy Award The Imperial Award, 2007 Milstein Award, 2009 Foreign Associate, National Academy of Science, 2009 Person of Cultural Merit, 2009 Hans Bloemendal Medal

Project Leader
  • Shizuo Akira, Professor
Research Members
  • Taro Kawai, Associate Professor
  • Osamu Takeuchi, Associate Professor
  • Satoshi Uematsu, Assistant Professor
  • Tatsuya Saito, Assistant Professor
  • Yutaro Kumagai, GCOE Assistant Professor

Summary

Our laboratory studies mechanisms of innate immunity. The innate immune system senses invading microbial pathogens and plays an essential role for induction of inflammatory responses as well as assisting adaptive immune responses. Germline-encoded pattern-recognition receptors (PRRs) expressed on innate immune cells such as macrophages and dendritic cells are responsible for recognition of pathogen-associated molecular patterns (PAMPs) which represent conserved molecular features in microbial pathogens. Through generation of knockout mice, we have demonstrated that a family of Toll-like receptors (TLR) recognizes a variety of PAMPs such as lipopolysaccharide, lipoprotein and nucleic acids derived from bacteria, viruses and protozoa怀to elicit innate immune responses. We have also demonstrated that a family of RIG-I-like RNA helicases (RLR) including RIG-I and MDA5 participates in TLR-independent recognition of nucleic acids derived from different types of RNA viruses in the cytoplasm. In addition, we have clarified in TLR signaling pathways that TLRs utilize different combinations of adapter molecules (MyD88, TRIF, TIRAP/Mal, TRAM) to activate different signaling pathways depending on the invading pathogen. Moreover, we have recently discovered an adapter molecule for RLR which we named IPS-1. Based on these findings, we are currently investigating following issues.

1) comprehensive analysis of gene expression in innate immune cells, using knockout mice.

2) discovery and characterization of functional molecules or cells regulating innate immune responses.

3) understanding of pathways linking between innate and adaptive immunity.

4) in vivo imaging of innate immune cells.

akira.jpg Figure 1: Pathogen recognition by TLRs.
TLRs recognize molecular patterns associated with a broad range of pathogens, including bacteria, fungi, protozoa and viruses.

Some of Recent Papers

  1. Saitoh T, Fujita N, Jang M-H, Uematsu S, Yang B-G, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264-268, 2008.
  2. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med. 2008 14:86-92.
  3. Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, Sato S, Tsujimura T, Yamamoto M, Yokota Y, Kiyono H, Miyasaka M, Ishii KJ, Akira S. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol. 2008 Jul;9(7):769-76.
  4. Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat. Immunol. 2008 9:684-91.
  5. Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, Uematsu S, Takeuchi O, Takeshita F, Coban C, Akira S. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature. 2008 Feb 7;451(7179):725-9.
  6. Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S.  Zc3h12a is an Rnase essential for controlling immune responses by regulating mRNA decay.  Nature. 2009 458:1185-9.
  7. Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S.  TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune rephritis. Nat Immunol. 2009 10:965-72.
  8. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S.  Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A. 2009 106:0842-6.
  9. Satoh T, Kato H, Kuamagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O.  LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci U S A. 2010 107:1512-7.
  10. Takeuchi O, Akira S.  Pattern recognition receptors and inflammation. Cell. 2010 140:805-20. Review.
  11. Kawai T, Akira S.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010 11:373-84.