Akiko Iwasaki PhD

Professor of Immunobiology and of Molecular, Cellular, and Developmental Biology; Professor of Molecular Cellular and Developmental Biology; Howard Hughes Medical Investigator

Research Interests

Innate immunity; Autophagy; Inflammasomes; Sexually transmitted infections; Herpes simplex virus; Human papillomavirus; Respiratory virus infections; Influenza infection; T cell immunity; Commensal bacteria


Research Summary

The mucosal surfaces represent major sites of entry for numerous infectious agents. Consequently, the vast mucosal surfaces are intricately lined with cells and lymphoid organs specialized in providing protective antibody and cellular immunity. One of the most fundamental issues in this field concerns how antigens in the mucosa are taken up, processed, and presented by antigen presenting cells. Our laboratory's goal is to understand how immunity is initiated and maintained at the mucosal surfaces, particularly by the dendritic cells (DCs), through natural portals of entry for pathogens that are of significant health concerns in the world.

We focus on understanding how viruses are recognized (innate immunity) and how that information is used to generate protective adaptive immunity. We study immune responses to herpes simplex viruses in the genital tract and influenza infection in the lung. Our recent focus also includes the study of how autophagy mediates innate and adaptive immune responses to these and other viral pathogens. Our ultimate goal is to utilize the knowledge we gain through these areas of research in the rational design of effective vaccines or microbicides for the prevention of transmission of viral and bacterial pathogens.

Extensive Research Description

Our research addresses mechanisms of innate recognition of viruses and initiation of antiviral immunity, particularly at the natural site of virus encounter at the mucosal surfaces.

Innate virus recognition and autophagy: The innate immune system has evolved to recognize invading pathogens through pattern recognition receptors (PRRs). Because viruses are synthesized by the host cell machinery, the nature of viral signatures recognized by PRRs was unclear. Our research revealed that viral nucleic acids from dsDNA and ssRNA viruses serve as a viral signature, and that they are recognized by endosomal Toll-like receptors (TLR)-9 and TLR-7, respectively in plasmacytoid dendritic cells (pDCs). Further, we demonstrated that in vivo, pDCs are required to secrete type I IFNs in response to genital herpes infection and mediate innate protection of the host. More recently, we discovered the role of autophagy in innate viral recognition. We demonstrated that TLR-7-mediated recognition of certain ssRNA viruses requires transport of cytosolic viral replication intermediates into the endosome by the process of autophagy in pDCs. This study demonstrated a link between innate viral recognition and autophagy. Unlike the pDCs, most other cell types recognize virus infection via the RIG-I-like receptors (RLRs) within the cytosol. In a recent study, we demonstrated that autophagy regulates RLR pathway by removal of damaged mitochondria. In the absence of autophagy, reactive oxygen species (ROS) accumulate within the mitochondria, and turn off regulation of RLR signaling. Thus, autophagy is essential in 1) delivering viral ligands to endosomal TLRs, and 2) clearing damaged mitochondria and ROS, thus regulating RLR signaling. We are currently investigating the mechanism by which ROS regulates RLR signaling.

Adaptive immunity to viruses: Innate recognition of viruses allows activation of adaptive immune responses. Dendritic cells (DCs) are potent inducers of T cell responses. However, how various populations of DCs sense virus infection and induce immune responses during a natural virus infection is unclear. OUr study demonstrated that submucosal DCs (beneath the epithelial layer), but not Langerhans cells (within the epithelial layer), are the primary inducers of Th1 immunity following genital herpes infection. Antigen presentation following mucosal viral infection is handled by the tissue-migrant submucosal DCs, while needle-introduced virus antigens are presented by lymphoid resident DCs . In addition to the direct activation of DCs by TLRs, we showed that DCs require TLR-dependent instructive signals from the infected cells in order to induce differentiation of effector T cells. We further demonstrated the requirement for TLR-dependent signal in enabling maximum screening of cognate lymphocytes during initiation of adaptive immunity through remodeling of the lymph node arteriole. Once initiated within the lymph nodes, effector Th1 cells travel to the site of infection and eliminate virus infection. Our recent study showed that the local mucosal DCs and B cells cooperate to restimulate Th1 cells to execute protective antiviral immunity. These studies collectively demonstrated the importance of tissue-DC interaction in the initiation of antiviral immunity. While the role of TLRs and RLRs in the initiation of adaptive immunity has been studied extensively, the role of NOD-like receptors (NLRs) in innate viral recognition and initiation of adaptive immune responses is unknown. Our recent study demonstrated that influenza virus infection triggers NLRs and it is required to elicit protective T cell and B cell immunity. We are currently using this information to design and develop novel vaccine strategies to better fight viral infections including HSV-2, influenza and human papillomavirus.



Selected Publications

  • Iwasaki A. Innate Immune Recognition of HIV-1. Immunity. 2012 Sep 21;37(3):389-98.
  • Iwasaki A. A virologic view of innate viral recognition. Annual review of microbiology 2012 Oct 13;66:177-96.
  • Yordy B, Iijima N, Huttner A, Leib D, Iwasaki A. A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus. Cell Host Microbe. 2012 Sep 13;12(3):334-45.
  • Kumamoto Y, Mattei LM, Sellers S, Payne GW, Iwasaki A. CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input. Proc Natl Acad Sci U S A. 2011 May 9.
  • Foxman, EF, and Iwasaki, A. Genome-virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol 2011 Apr;9(4):254-64.
  • Ichinohe, T., Pang, IK, Kumamoto, Y., Peaper, DR, Ho, JH, Murray, TS, and Iwasaki, A. Microbiota regulates immune defense against respiratory tract influenza A virus infection Proc. Natl. Acad. Sci. 2011 Mar 29;108(13):5354-9.
  • Sasai M, Linehan MM, Iwasaki A. Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 2010 Sep 17;329(5998):1530-4.
  • Influenza virus activates inflammasomes via its intracellular M2 ion channel. Ichinohe T, Pang IK, Iwasaki A. Nat Immunol. 2010 May;11(5):404-10.
  • In Vivo Requirement for Atg5 in Antigen Presentation by Dendritic Cells. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A. Immunity. 2010 Feb 26;32(2):227-239.
  • Iwasaki, A., and R. Medzhitov. Regulation of adaptive immunity by the innate immune system. Science 327:291-295, 2010.

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