Research

Research Theme

The Project Leader's Profile

Hisashi Arase

Professor, Laboratory of Immunochemistry, WPI Immunology Frontier Research Center,
Osaka University

1990 School of Medicine, Hokkaido University  
1994 Graduate School of Medicine Hokkaido University 1994 Research Associate,
     Chiba University School of Medicine
2000 Research Fellow, University of California San Francisco
2002 Associate Professor, Chiba University Graduate School of Medicine
2004 Associate Professor, Research Institute for Microbial Diseases, Osaka University
2006 Professor, Research Institute for Microbial Diseases, Osaka University
2007 Professor, WPI Immunology Frontier Research Center, Osaka University

Project Leader
  • Hisashi Arase (M.D.,Ph.D.), Professor, Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University
Research Members
  • Tadahiro Suenaga, Assistant professor
  • Takeshi Satoh, Assistant professor
  • Fumiji Saito, COE Research fellow
Research Collaborators
  • Junji Uehori, Research fellow

Summary

Our department analyzes how pathogens such as viruses have acquired the ability to evade the immune system and how host immune systems have acquired resistance to various pathogens. In particular, we are elucidating a fundamental mechanism of host defense against various pathogens by analyzing various immune regulatory receptors. Of particular interest are 'paired receptors' that consist of activating and inhibitory receptors expressed on various immune cells. We have suggested that these 'paired receptors' have evolved with pathogens by identifying the host ligands and viral ligands they recognize. In addition, we have found that these receptors are also involved in viral entry into cells. These studies will help to elucidate fundamental mechanisms of immune evasion by pathogen and the host factors that influence resistance to various infections. This research will help to build the foundation required for the development of new vaccines and therapies for infectious diseases.

(1) Analysis of recognition by 'paired receptors'
Immune cells express various receptors that consist of activating and inhibitory receptors that are highly homologous to each other. The inhibitory receptors recognize self-antigens such as MHC molecules. In contrast, the activating receptors generally do not recognize self-antigens and ligands for most of them have remained unclear. We have found that one of these 'paired receptors' recognizes cytomegalovirus protein and showed that 'paired receptors' play an important role in determining host resistance to pathogens. We are continuing to analyze the functions of these receptors to elucidate the interactions between pathogens and the host immune system.

(2) Entry mechanism of virus into cells
As described above, several viruses, which show persistent infection, downregulate immune response by expressing ligands for inhibitory receptors. Interestingly, we have found that some viruses exploit inhibitory receptors to enter the cells. Interaction between immune receptors and viral proteins was found to play an important role in entry mechanism of herpes simplex virus (HSV) (Figure). Because there is a possibility that other viruses also use similar receptors to enter cells, we further investigate molecular mechanisms involved in viral entry into cells. 
Figure 3-1.jpgFigure
Entry mechanism of virus into cells
Some viruses express ligands for inhibitory receptors and downregulate immune response.  We found that PILRa, one of inhibitory paired receptors, recognizes herpes simplex virus (HSV) infected cells.  Molecular cloning of the ligands for PILRa revealed that PILRa recognizes HSV glycoprotein B that plays an essential role in HSV infection.  Furthermore, interaction between PILRa and glycoprotein B was found to be involved in viral entry into cells.  On the other hand, we also found that glycoprotein B of varicella-zoster virus associates with myelin associated glycoprotein (MAG, Siglec-4), one of paired receptors, and the association mediates VZV entry into cells.  In this way, paired receptors play important roles not only in immune regulation but also in viral entry into cells.  

Some of Recent Papers

1.        Suenaga, T., Satoh, T., Somboonthum, P., Kawaguchi, Y., Mori, Y., and Arase, H. Myelin-associated glycoprotein mediates membrane fusion and entry of neurotropic herpesviruses. Proc. Natl. Acad. Sci. USA 107:866-871. (2010)

2.        Wang, J., Fan, F., Satoh, T., Arii, J., Lanier, L.L., Spear, P.G., Kawaguchi, Y., Arase, H. Binding of herpes simplex virus glycoprotein B (gB) to PILRα depends on specific sialylated O-linked glycans on gB J. Virol. 83:13042-13045. (2009)

3.        Arii, J., Uema, M., Morimoto, T., Sagara, H., Akashi, H., Ono, E., Arase, H., and Kawaguchi, Y. Entry of herpes simplex virus 1 and other alphaherpesviruses via the paired immunoglobulin-like type 2 receptor α. J. Virol. 83:4520-4527. (2009)

4.        Fan, Q., Lin, E., Satoh, T., Arase, H., and Spear, P.G. Differential effects on cell fusion activity of mutations in herpes simplex virus 1 glycoprotein B (gB) dependent on whether a gD receptor or a gB receptor is overexpressed. J. Virol. 83:7384-7390. (2009)

5.        Orr, M.T., Sun, J.C., Hesslein, D.G., Arase, H., Phillips, J.H., Takai, T., and Lanier, L.L. Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infection. J. Exp. Med. 206:807-817. (2009)

6.        Satoh, T., Arii, J., Suenaga, T., Wang, J., Kogure, A., Uehori, J., Arase, N., Shiratori, I., Tanaka, S., Kawaguchi, Y., Spear, P.G., Lanier, L.L. and Arase, H. PILRα is a herpes simplex virus-1 entry co-receptor that associates with glycoprotein B. Cell 132:935-944 .(2008)

7.        Wang, J., Shiratori, I., Satoh, T., Lanier, L.L., and Arase, H.  An essential role of sialylated O-linked sugar chains in the recognition of mouse CD99 by paired immunoglobulin-like type 2 receptor (PILR). J. Immunol. 180:1686-1693. (2008)

8.        Shiratori, I., Yamaguchi, M., Suzukawa, M., Yamamoto, K., Lanier, L.L., Saito, T. and Arase, H. Downregulation of basophil function by human CD200 and human herpesvirus-8 CD200. J. Immunol. 175:4441-4449. (2005)

9.        Shiratori, I., Ogasawara, K., Saito, T., Lanier, L. L., and Arase, H. Activation of natural killer cells and dendritic cells upon recognition of a novel CD99-like ligand by paired immunoglobulin-like type 2 receptor. J. Exp. Med. 199:525-533. (2004)