Dr. Akiko Iwasaki |
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Yale University School of Medicine Immunobiology Associate Professor |  |
Mailing AddressDepartment of Immunobiology Yale University School of Medicine 300 Cedar Street TAC S655B New Haven, Connecticut 06520-8011United States | Contact Information |
Qualifications
Ph.D., University of Toronto, Immunology, 1998.
B.Sc., University of Toronto, Biochemistry and Physics, 1994.
Expertise and Research Interests
Research in my laboratory focuses on understanding the mechanism of innate recognition of viruses and how signals downstream of pattern recognition leads to adaptive immune responses. We are particularly interested in understanding these events as they take place at the mucosal surfaces during infection by viruses through their natural route of entry . The key questions in this regard relate to how pathogens are recognized, taken up and presented by the professional antigen-presenting cells. Our research is aimed at defining immune inductive mechanism at the levels of a whole organism (host), cellular (dendritic cell subsets) and molecular (specific receptors that recognize the virus and activate dendritic cells) levels.
Innate recognition of viruses occur through distinct pathways involving Toll like receptors (TLRs) in the endosomes and RIG-I like receptors (RLR) in the cytosol. We have demonstrated that in plasmacytoid dendritic cells, dsDNA viruses and ssRNA viruses are recognized by TLR9 and TLR7 respectively. More recent work demonstrated that certain ssRNA viruses are detected by TLR7 upon delivery of cytosolic viral replication intermediates via autophagy. We are currently engaged in dissecting the mechanism by which autophagy regulates viral recognition in multiple systems.
To understand how innate recognition leads to adaptive immunity following viral infections in vivo, we are examining the role of dendritic cells in immune induction to Herpes simplex virus (HSV)-2 using a mouse model for genital herpes infection. We found that early during HSV-2 infection, dendritic cells are recruited to submucosa beneath the infected vaginal epithelial cells through recognition of inflammatory chemokines. These submucosal CD11b+ DCs recognize the virus through pathogen associated pattern recognition receptors, become activated, take up virus antigens and present them to naïve CD4+ T cells in the draining lymph nodes. This interaction between the CD11b+ dendritic cells and the CD4+ T cells is crucial in the generation of Th1 response required for the clearance of the virus infection. Aside from the CD11b+ dendritic cells that initiate Th1 responses to HSV-2, another subset of dendritic cells known as the plasmacytoid dendritic cells are critical in providing type I interferons early during infection at the site of virus entry. Importantly, we found that innate recognition of HSV-2 by dendritic cells is not sufficient to prime Th1 responses, but that innate recognition by the infected vaginal epithelial cells is also required for this process. These findings are important in the context of not only HSV-2 but also of other sexually transmitted viral pathogens such as HIV. In the future, we hope to utilize the understanding of how immunity is generated against sexually transmitted disease agents for rational design of effective mucosal vaccines and microbicides.
Innate recognition of viruses occur through distinct pathways involving Toll like receptors (TLRs) in the endosomes and RIG-I like receptors (RLR) in the cytosol. We have demonstrated that in plasmacytoid dendritic cells, dsDNA viruses and ssRNA viruses are recognized by TLR9 and TLR7 respectively. More recent work demonstrated that certain ssRNA viruses are detected by TLR7 upon delivery of cytosolic viral replication intermediates via autophagy. We are currently engaged in dissecting the mechanism by which autophagy regulates viral recognition in multiple systems.
To understand how innate recognition leads to adaptive immunity following viral infections in vivo, we are examining the role of dendritic cells in immune induction to Herpes simplex virus (HSV)-2 using a mouse model for genital herpes infection. We found that early during HSV-2 infection, dendritic cells are recruited to submucosa beneath the infected vaginal epithelial cells through recognition of inflammatory chemokines. These submucosal CD11b+ DCs recognize the virus through pathogen associated pattern recognition receptors, become activated, take up virus antigens and present them to naïve CD4+ T cells in the draining lymph nodes. This interaction between the CD11b+ dendritic cells and the CD4+ T cells is crucial in the generation of Th1 response required for the clearance of the virus infection. Aside from the CD11b+ dendritic cells that initiate Th1 responses to HSV-2, another subset of dendritic cells known as the plasmacytoid dendritic cells are critical in providing type I interferons early during infection at the site of virus entry. Importantly, we found that innate recognition of HSV-2 by dendritic cells is not sufficient to prime Th1 responses, but that innate recognition by the infected vaginal epithelial cells is also required for this process. These findings are important in the context of not only HSV-2 but also of other sexually transmitted viral pathogens such as HIV. In the future, we hope to utilize the understanding of how immunity is generated against sexually transmitted disease agents for rational design of effective mucosal vaccines and microbicides.
Keywords
COS Keywords:
Epidemiology, Gastroenterology, Infectious Diseases or Agents, Urogenital System, Vaccine.Additional Terms:
Antiviral Immunity, Autophagy, Genital Mucosa, Herpes Simplex Virus, Influenza Virus, Innate Immunity, Intestinal Mucosa, Mucosal Dendritic Cells, Toll Like Receptor.Languages
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
Japanese: (Fluent, Fluent, Fluent)
Memberships
American Association of Immunologists
American Society of Microbiology
Canadian Society for Immunology
Infectious Diseases Society of America
Society for Mucosal Immunology
Publications
- Lee HK, Iwasaki A (2008) Autophagy and antiviral immunity, Current Opinion in Immunology, 20, 23-29
- Thompson JM, Iwasaki A (2007) Toll-like receptors regulation of viral infection and disease, Advanced Drug Delivery Review, 60, 786-94
- Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK, Mizushima NN, Iwasaki A, He YW, Swat W,, Virgin HW (2007) The autophagy gene ATG5 plays an essential role in B lymphocyte development, Autophagy, 4 (3), 309-14
- Iijima N, Linehan MM, Saeland S, Iwasaki A (2007) Vaginal epithelial dendritic cells renew from bone marrow precursors, Proc. Natl. Acad. Sci, 104, 19061-19066
- Iwasaki, A. (2007) Role of Autophagy in Innate Viral Recognition, Autophagy, 3, 354-356
- Iwasaki, A. (2007) Division of labor by dendritic cells, Cell, 128:, 435-436
- Lee HK, Iwasaki A (2007) Innate control of adaptive immunity: dendritic cells and beyond, Seminar in Immunology, 19 (1), 48-55
- Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells, Science, 2007, 315 (5817), 1398-1401
- Iwasaki, A. (2007) Mucosal dendritic cells, Annual Review of Immunology, 25, 381-418
- Lund, J., Linehan, M.M., Iijima N., Iwasaki, A. (2006) Cutting Edge: Plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ, Journal of Immunology, 177, 7510-7514
- Sato, A, Linehan, M. M, Iwasaki, A (2006) Dual Recognition of Herpes Simplex Viruses by TLR2 and TLR9 in Dendritic Cells., Proc. Natl. Acad. Sci, 103 (46), 17343-17348
- Shen, H, Iwasaki, A (2006) A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide., Journal of Clinical Investigation, 116 (8), 2237-2243
- Soderberg, KA, Payne, GW, Sato, A, Medzhitov, R, Segal, SS, Iwasaki, A (2005) Innate control of adaptive immunity via remodeling of lymph node feed arteriole., Proceedings of the National Academy of Sciences of the United States of America, 102 (45), 16315-16320
- Sato A, Iwasaki A, Induction of antiviral immunity requires Toll-like receptor signaling in
both stromal and dendritic cell compartments, Proceedings of the National Academy of Sciences of the United States of America., 101(46), 16274-9, Nov 2004
- Iwasaki A, Medzhitov R, Toll-like receptor control of the adaptive immune responses, Nature Immunology, 5(10), 987-95, Oct 2004
- Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA, Recognition of single-stranded RNA viruses by Toll-like receptor 7, Proceedings of the National Academy of Sciences of the United States of America., 101(15), 5598-603, April 2004
- Linehan MM, Richman S, Krummenacher C, Eisenberg RJ, Cohen GH, Iwasaki A, In vivo role of nectin-1 in entry of herpes simplex virus type 1 (HSV-1)
and HSV-2 through the vaginal mucosa, Journal of Virology, 78(5), 2530-6, March 2004
- Iwasaki A, The role of dendritic cells in immune responses against vaginal infection
by herpes simplex virus type 2, Microbes and Infection / Institut Pasteur, 5(13), 1221-30, November 2003
- Zhao X, Sato A, Dela Cruz CS, Linehan M, Luegering A, Kucharzik T, Shirakawa AK, Marquez G, Farber JM, Williams I, Iwasaki A, CCL9 is secreted by the follicle-associated epithelium and recruits dome
region Peyer's patch CD11b+ dendritic cells, Journal of Immunology (baltimore, Md. : 1950), 171(6), 2797-803, September 2003
- Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A, Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by
plasmacytoid dendritic cells, Journal of Experimental Medicine, 198(3), 513-20, August 2003
- Iwasaki A, The importance of CD11b+ dendritic cells in CD4+ T cell activation in
vivo: with help from interleukin 1, Journal of Experimental Medicine, 198(2), 185-90, July 2003
- Zhao X, Deak E, Soderberg K, Linehan M, Spezzano D, Zhu J, Knipe DM, Iwasaki A, Vaginal submucosal dendritic cells, but not Langerhans cells, induce
protective Th1 responses to herpes simplex virus-2, Journal of Experimental Medicine, 197(2), 153-62, January 2003
- Iwasaki A, Kelsall BL, Unique functions of CD11b , CD8 alpha , and double-negative Peyer's patch dendritic cells, Journal of Immunology, 166(8), 4884-90, 2001
- Iwasaki A, Kelsall BL, Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine, Journal of Experimental Medicine, 191(8), 1381-94, April 2000
- Iwasaki A, Kelsall BL, Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells, Journal of Experimental Medicine, 190(2), 229-39, July 1999
Profile Details
Last Updated: 8/20/2008
COS Expertise ID #906303
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