Autophagy; Herpes Simplex; Immune System; Immunity, Cellular; Immunity, Innate; Influenza, Human; Molecular Biology; Sexually Transmitted Diseases; Inflammasomes
Molecular Virology: Virology laboratories
Skin Diseases Research Center, Yale
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. We focus on understanding how viruses are recognized by the cells of the innate immune system 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 virus and rhinovirus infection in the lung. Our studies probe the mechanism of protection provided by the memory T cells that reside within the mucosal organs, known as tissue resident memory T cells, and use this information to design better vaccines. We developed a new vaccine strategy, "Prime and Pull" in which memory T cells can be established at the mucosal surface targeted by viruses. Prime and Pull confers better protection against genital herpes than conventional vaccine approaches. 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 pathogens and possible treatment of cancers.
Specialized Terms: Innate immunity; Autophagy; Inflammasomes; Sexually transmitted infections; Herpes simplex virus; Human papillomavirus; Respiratory virus infections; Influenza infection; T cell immunity; Commensal bacteria
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, autophagy and signaling: 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. 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. More recently, we identified a lysosome-related organelle from which both TLR7 and TLR9 traffic to signal for interferon production and demonstrated that TLR traffic to this compartment is mediated by the adaptor protein AP-3. AP-3 recruitment to the TLR9 endosome requires activity of PIKfyve, an enzyme that phosphorylates PI3P to form PI(3,5)P2 on endosomal membrane.
Temperature control of innate immune response to viruses: we found that temperature can alter the ability of the airway cells to mount an effective innate immune response against rhinovirus, the common cold virus. Airway epithelial cells, the cells that form the lining of the nose and the other airways, are the main target of rhinovirus infection. In order to amplify, spread, and cause disease, the virus must enter these cells and make more copies of itself. By studying airway cells incubated at different temperatures, we discovered that mechanisms used by the innate immune system to protect cells against this virus are quite effective at core body temperature (37°C), but are greatly diminished at slightly cooler temperatures, such as temperatures that might be found in the nasal passages upon inhaling cool ambient air (33°C). The temperature-dependent signals included those involved in the recognition of the replicating virus inside the cell (the RIG-I like receptor pathway) as well as the signals required for turning on antiviral defenses following viral recognition (the Type I interferon response.) These signals are important in immune defense against many viruses, and future studies may reveal that lower temperature provides an opportunity for other viruses that infect the airways or other cool areas of the body to evade antiviral defenses.
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.
Tissue resident memory T cells: Adaptive immune response to pathogens generates effector T cells with diverse functions. While the majority of effector T cells engage in pathogen control during primary infection, a subset of effector T cells differentiates into memory T cells critical for controlling future infections. Recent studies have revealed that a small subset of effector T cells seed the lymphoid and non-lymphoid tissues and establish residency. Precursors of tissue-resident memory T cells (TRM) receive critical cues from the tissue for migration and residency. We demonstrated that CD4 T cells 'help" the CD8 T effector cells enter the tissue through their secretion of IFN-g and induction of CXCL9 and CXCL10 that bind to CXCR3 expressed by teh CD8 effector T cells. We also demonstrated that TRM can reside within the epithelial layer, or be housed subepithelially in a structure known as memory lymphocyte clusters (MLCs). MLCs are self-sustaining home to the TRMand are supported by the local macrophages that secrete retention signals. Importantnly, CD4 and CD8 TRM provide potent protection against viral challenge compared to circulating memory counterparts. Based on this understanding, we developed a new vaccine strategy we call "Prime and Pull". This vaccine works in two steps. First, we prime T cell responses using conventional vaccines. Second, we "pull" in the T cells to the organ of choice using chemokines that we now know are capable of recruiting such cells (CXCL9 and CXCL10). The Prime and Pull vaccine provides much better protection against genital herpes infection than conventional vaccine alone, because it establishes CD8 TRM at the site of pathogen entry. This understanding for CD8 T cell access can be harnessed to enable T cell entry into solid tumors, which has direct implications for cancer immunotherapy.
T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells.
Iijima N and Iwasaki A: T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014 Oct 3;346 (6205) :93-8.
A vaccine strategy that protects against genital herpes by establishing local memory T cells.
Shin H and Iwasaki A: A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012 Nov 15;491 (7424) :463-7.
Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.
Foxman EF, Storer JA, Fitzgerald ME, Wasik BR, Hou L, Zhao H, Turner PE, Pyle AM and Iwasaki A. PNAS, January 5, 2015 DOI: 10.1073/pnas.1411030112
Control of adaptive immunity by the innate immune system.
Iwasaki A and Medzhitov R: Control of adaptive immunity by the innate immune system. Nat Immunol. 2015 Apr;16 (4) :343-53.
CD301b⁺ dermal dendritic cells drive T helper 2 cell-mediated immunity.
Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE and Iwasaki A: CD301b? dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity. 2013 Oct 17;39 (4) :733-43.
IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8⁺ T cell responses to influenza A virus.
Pang IK, Ichinohe T and Iwasaki A: IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8? T cell responses to influenza A virus. Nat Immunol. 2013 Mar;14 (3) :246-53.
Innate Immune Recognition of HIV-1. Immunity.
Iwasaki A. Innate Immune Recognition of HIV-1. Immunity. 2012 Sep 21;37(3):389-98.
A virologic view of innate viral recognition.
Iwasaki A. A virologic view of innate viral recognition. Annual review of microbiology 2012 Oct 13;66:177-96.
A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus.
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.
Genome-virome interactions: examining the role of common viral infections in complex disease.
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.
Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3.
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.
In Vivo Requirement for Atg5 in Antigen Presentation by Dendritic Cells.
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.
CTL mobilization to virus-infected tissue requires CD4+ T cell help.
Nakanishi, Y., Lu, B., Gerard, C., Iwasaki, A. CTL mobilization to virus-infected tissue requires CD4+ T cell help. Nature, 2009 462(7272):510-3.
Full List of PubMed Publications
- Gibb DR, Liu J, Natarajan P, Santhanakrishnan M, Madrid DJ, Eisenbarth SC, Zimring JC, Iwasaki A, Hendrickson JE: Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice. J Immunol. 2017 Aug 1; 2017 Jun 19. PMID: 28630094
- Sasai M, Sakaguchi N, Ma JS, Nakamura S, Kawabata T, Bando H, Lee Y, Saitoh T, Akira S, Iwasaki A, Standley DM, Yoshimori T, Yamamoto M: Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense. Nat Immunol. 2017 Aug; 2017 Jun 12. PMID: 28604719
- Chen YG, Kim MV, Chen X, Batista PJ, Aoyama S, Wilusz JE, Iwasaki A, Chang HY: Sensing Self and Foreign Circular RNAs by Intron Identity. Mol Cell. 2017 Jul 20; 2017 Jun 15. PMID: 28625551
- Fink SL, Jayewickreme TR, Molony RD, Iwawaki T, Landis CS, Lindenbach BD, Iwasaki A: IRE1α promotes viral infection by conferring resistance to apoptosis. Sci Signal. 2017 Jun 6; 2017 Jun 6. PMID: 28588082
- Uraki R, Jurado KA, Hwang J, Szigeti-Buck K, Horvath T, Iwasaki A, Fikrig E: Sexual transmission of ZIKV causes fetal growth restriction in mice. J Infect Dis. 2017 May 2; 2017 May 2. PMID: 28472297
- Hastings AK, Yockey LJ, Jagger BW, Hwang J, Uraki R, Gaitsch HF, Parnell LA, Cao B, Mysorekar IU, Rothlin CV, Fikrig E, Diamond MS, Iwasaki A: TAM Receptors Are Not Required for Zika Virus Infection in Mice. Cell Rep. 2017 Apr 18. PMID: 28423319
- Iwasaki A: Immune Regulation of Antibody Access to Neuronal Tissues. Trends Mol Med. 2017 Mar; 2017 Feb 7. PMID: 28185790
- Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD: β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep. 2017 Feb 28. PMID: 28249154
- Uraki R, Hwang J, Jurado KA, Householder S, Yockey LJ, Hastings AK, Homer RJ, Iwasaki A, Fikrig E: Zika virus causes testicular atrophy. Sci Adv. 2017 Feb; 2017 Feb 22. PMID: 28261663
- Iwasaki A, Foxman EF, Molony RD: Early local immune defences in the respiratory tract. Nat Rev Immunol. 2017 Jan; 2016 Nov 28. PMID: 27890913
- Shin H, Kumamoto Y, Gopinath S, Iwasaki A: CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2. Nat Commun. 2016 Nov 9; 2016 Nov 9. PMID: 27827367
- Kumamoto Y, Hirai T, Wong PW, Kaplan DH, Iwasaki A: CD301b+ dendritic cells suppress T follicular helper cells and antibody responses to protein antigens. Elife. 2016 Sep 22; 2016 Sep 22. PMID: 27657168
- Kumamoto Y, Camporez JP, Jurczak MJ, Shanabrough M, Horvath T, Shulman GI, Iwasaki A: CD301b(+) Mononuclear Phagocytes Maintain Positive Energy Balance through Secretion of Resistin-like Molecule Alpha. Immunity. 2016 Sep 20; 2016 Aug 23. PMID: 27566941
- Shook B, Xiao E, Kumamoto Y, Iwasaki A, Horsley V: CD301b+ Macrophages Are Essential for Effective Skin Wound Healing. J Invest Dermatol. 2016 Sep; 2016 Jun 7. PMID: 27287183
- Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, Iwasaki A: Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell. 2016 Aug 25. PMID: 27565347
- Foxman EF, Storer JA, Vanaja K, Levchenko A, Iwasaki A: Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature. Proc Natl Acad Sci U S A. 2016 Jul 26; 2016 Jul 11. PMID: 27402752
- Schmid ET, Pang IK, Carrera Silva EA, Bosurgi L, Miner JJ, Diamond MS, Iwasaki A, Rothlin CV: AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity. Elife. 2016 Jun 28; 2016 Jun 28. PMID: 27350258
- Khoury-Hanold W, Yordy B, Kong P, Kong Y, Ge W, Szigeti-Buck K, Ralevski A, Horvath TL, Iwasaki A: Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality. Cell Host Microbe. 2016 Jun 8. PMID: 27281569
- Iwasaki A: Antiviral responses of inbred mice. Nat Rev Immunol. 2016 Jun; 2016 Apr 25. PMID: 27108522
- Iijima N, Iwasaki A: Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature. 2016 May 26; 2016 May 18. PMID: 27225131
- Iwasaki A: Exploiting Mucosal Immunity for Antiviral Vaccines. Annu Rev Immunol. 2016 May 20. PMID: 27168245
- Pillai PS, Molony RD, Martinod K, Dong H, Pang IK, Tal MC, Solis AG, Bielecki P, Mohanty S, Trentalange M, Homer RJ, Flavell RA, Wagner DD, Montgomery RR, Shaw AC, Staeheli P, Iwasaki A: Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science. 2016 Apr 22. PMID: 27102485
- Gopinath S, Kumamoto Y, Iwasaki A: O-linked sugars sound the alarm. Nat Immunol. 2016 Feb. PMID: 26784258
- Khoury-Hanold W, Iwasaki A: Autophagy Snuffs a Macrophage's Inner Fire. Cell Host Microbe. 2016 Jan 13. PMID: 26764592
- Hayashi K, Sasai M, Iwasaki A: Toll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity. Int Immunol. 2015 Sep; 2015 Apr 29. PMID: 25925170
- Iijima N, Iwasaki A: Tissue instruction for migration and retention of TRM cells. Trends Immunol. 2015 Sep; 2015 Aug 14. PMID: 26282885
- Iwasaki A: Balancing family life with a science career. Nat Immunol. 2015 Aug. PMID: 26194275
- Gopinath S, Iwasaki A: Cervicovaginal microbiota: simple is better. Immunity. 2015 May 19. PMID: 25992855
- West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, Kaech SM, Smiley JR, Means RE, Iwasaki A, Shadel GS: Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015 Apr 23; 2015 Feb 2. PMID: 25642965
- Saglam O, Samayoa E, Somasekar S, Naccache S, Iwasaki A, Chiu CY: No viral association found in a set of differentiated vulvar intraepithelial neoplasia cases by human papillomavirus and pan-viral microarray testing. PLoS One. 2015; 2015 Apr 20. PMID: 25894343
- Iwasaki A, Medzhitov R: Control of adaptive immunity by the innate immune system. Nat Immunol. 2015 Apr. PMID: 25789684
- Kashem SW, Igyarto BZ, Gerami-Nejad M, Kumamoto Y, Mohammed JA, Jarrett E, Drummond RA, Zurawski SM, Zurawski G, Berman J, Iwasaki A, Brown GD, Kaplan DH: Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity. 2015 Feb 17; 2015 Feb 10. PMID: 25680275
- Foxman EF, Storer JA, Fitzgerald ME, Wasik BR, Hou L, Zhao H, Turner PE, Pyle AM, Iwasaki A: Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells. Proc Natl Acad Sci U S A. 2015 Jan 20; 2015 Jan 5. PMID: 25561542
- Lipovsky A, Zhang W, Iwasaki A, DiMaio D: Application of the proximity-dependent assay and fluorescence imaging approaches to study viral entry pathways. Methods Mol Biol. 2015. PMID: 25702134
- Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY, Taniguchi T, Shadel GS, Chen ZJ, Iwasaki A, Flavell RA: Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014 Dec 18. PMID: 25525875
- Iijima N, Iwasaki A: T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014 Oct 3; 2014 Aug 28. PMID: 25170048
- Khan S, Toyoda H, Linehan M, Iwasaki A, Nomoto A, Bernhardt G, Cello J, Wimmer E: Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation. J Gen Virol. 2014 Aug; 2014 Apr 30. PMID: 24784416
- Iwasaki A, Pillai PS: Innate immunity to influenza virus infection. Nat Rev Immunol. 2014 May. PMID: 24762827
- Guo YE, Riley KJ, Iwasaki A, Steitz JA: Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function. Mol Cell. 2014 Apr 10. PMID: 24725595
- Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan JC: A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell. 2014 Feb 13. PMID: 24529375
- Ding S, Khoury-Hanold W, Iwasaki A, Robek MD: Epigenetic reprogramming of the type III interferon response potentiates antiviral activity and suppresses tumor growth. PLoS Biol. 2014 Jan; 2014 Jan 7. PMID: 24409098
- You F, Wang P, Yang L, Yang G, Zhao YO, Qian F, Walker W, Sutton R, Montgomery R, Lin R, Iwasaki A, Fikrig E: ELF4 is critical for induction of type I interferon and the host antiviral response. Nat Immunol. 2013 Dec; 2013 Nov 3. PMID: 24185615
- Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A: CD301b⁺ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity. 2013 Oct 17; 2013 Sep 26. PMID: 24076051
- Shin H, Iwasaki A: Generating protective immunity against genital herpes. Trends Immunol. 2013 Oct; 2013 Sep 3. PMID: 24012144
- Shin H, Iwasaki A: Tissue-resident memory T cells. Immunol Rev. 2013 Sep. PMID: 23947354
- Iijima N, Goodwin EC, Dimaio D, Iwasaki A: High-risk human papillomavirus E6 inhibits monocyte differentiation to Langerhans cells. Virology. 2013 Sep; 2013 Jul 18. PMID: 23871219
- Pang IK, Pillai PS, Iwasaki A: Efficient influenza A virus replication in the respiratory tract requires signals from TLR7 and RIG-I. Proc Natl Acad Sci U S A. 2013 Aug 20; 2013 Aug 5. PMID: 23918369
- Mattei LM, Cotmore SF, Tattersall P, Iwasaki A: Parvovirus evades interferon-dependent viral control in primary mouse embryonic fibroblasts. Virology. 2013 Jul 20; 2013 May 12. PMID: 23676303
- Mattei LM, Cotmore SF, Li L, Tattersall P, Iwasaki A: Toll-like receptor 9 in plasmacytoid dendritic cells fails to detect parvoviruses. J Virol. 2013 Mar; 2013 Jan 9. PMID: 23302877
- Pang IK, Ichinohe T, Iwasaki A: IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8⁺ T cell responses to influenza A virus. Nat Immunol. 2013 Mar; 2013 Jan 13. PMID: 23314004
- Hayashi K, Iwasaki A: Different routes to the same destination. Elife. 2013 Feb 19; 2013 Feb 19. PMID: 23426937
- Yordy B, Iwasaki A: Cell type-dependent requirement of autophagy in HSV-1 antiviral defense. Autophagy. 2013 Feb 1; 2012 Oct 24. PMID: 23095715
- Yordy B, Tal MC, Hayashi K, Arojo O, Iwasaki A: Autophagy and selective deployment of Atg proteins in antiviral defense. Int Immunol. 2013 Jan; 2012 Oct 5. PMID: 23042773
- Henault J, Martinez J, Riggs JM, Tian J, Mehta P, Clarke L, Sasai M, Latz E, Brinkmann MM, Iwasaki A, Coyle AJ, Kolbeck R, Green DR, Sanjuan MA: Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity. 2012 Dec 14; 2012 Dec 6. PMID: 23219390
- Shin H, Iwasaki A: A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012 Nov 15; 2012 Oct 17. PMID: 23075848
- Iwasaki A: Innate immune recognition of HIV-1. Immunity. 2012 Sep 21. PMID: 22999945
- 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. PMID: 22980330
- Shin H, Iwasaki A: Skin T(RM) mediates distributed border patrol. Cell Res. 2012 Sep; 2012 May 8. PMID: 22565287
- Kumamoto Y, Iwasaki A: Unique features of antiviral immune system of the vaginal mucosa. Curr Opin Immunol. 2012 Aug; 2012 Jun 4. PMID: 22673876
- Iwasaki A: A virological view of innate immune recognition. Annu Rev Microbiol. 2012. PMID: 22994491
- Pang IK, Iwasaki A: Control of antiviral immunity by pattern recognition and the microbiome. Immunol Rev. 2012 Jan. PMID: 22168422
- Hoshi N, Schenten D, Nish SA, Walther Z, Gagliani N, Flavell RA, Reizis B, Shen Z, Fox JG, Iwasaki A, Medzhitov R: MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nat Commun. 2012. PMID: 23047678
- Iwasaki A, Medzhitov R: A new shield for a cytokine storm. Cell. 2011 Sep 16. PMID: 21925310
- Yordy B, Iwasaki A: Autophagy in the control and pathogenesis of viral infection. Curr Opin Virol. 2011 Sep. PMID: 21927636
- Tal MC, Iwasaki A: Mitoxosome: a mitochondrial platform for cross-talk between cellular stress and antiviral signaling. Immunol Rev. 2011 Sep. PMID: 21884179
- Sasai M, Iwasaki A: Love triangle between Unc93B1, TLR7, and TLR9 prevents fatal attraction. Immunity. 2011 Jul 22. PMID: 21777792
- 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 24; 2011 May 9. PMID: 21555577
- Foxman EF, Iwasaki A: Genome-virome interactions: examining the role of common viral infections in complex disease. Nat Rev Microbiol. 2011 Apr. PMID: 21407242
- Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A: Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011 Mar 29; 2011 Mar 14. PMID: 21402903
- Iijima N, Mattei LM, Iwasaki A: Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proc Natl Acad Sci U S A. 2011 Jan 4; 2010 Dec 20. PMID: 21173243
- Pang IK, Iwasaki A: Inflammasomes as mediators of immunity against influenza virus. Trends Immunol. 2011 Jan; 2010 Dec 14. PMID: 21147034
- Iwasaki A: Antiviral immune responses in the genital tract: clues for vaccines. Nat Rev Immunol. 2010 Oct; 2010 Sep 10. PMID: 20829886
- Sasai M, Linehan MM, Iwasaki A: Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science. 2010 Sep 17. PMID: 20847273
- Ichinohe T, Pang IK, Iwasaki A: Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol. 2010 May; 2010 Apr 11. PMID: 20383149
- Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A: In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity. 2010 Feb 26; 2010 Feb 18. PMID: 20171125
- Iwasaki A, Medzhitov R: Regulation of adaptive immunity by the innate immune system. Science. 2010 Jan 15. PMID: 20075244
- Nakanishi Y, Lu B, Gerard C, Iwasaki A: CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature. 2009 Nov 26; 2009 Nov 8. PMID: 19898495
- Wang Z, Kumamoto Y, Wang P, Gan X, Lehmann D, Smrcka AV, Cohn L, Iwasaki A, Li L, Wu D: Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5. J Biol Chem. 2009 Oct 16; 2009 Aug 27. PMID: 19713215
- Tal MC, Iwasaki A: Autophagic control of RLR signaling. Autophagy. 2009 Jul. PMID: 19571662
- Ichinohe T, Iwasaki A: [Inflammasomes in viral infection]. Uirusu. 2009 Jun. PMID: 19927984
- Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A: Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A. 2009 Feb 24; 2009 Feb 5. PMID: 19196953
- Lee HK, Zamora M, Linehan MM, Iijima N, Gonzalez D, Haberman A, Iwasaki A: Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection. J Exp Med. 2009 Feb 16; 2009 Jan 19. PMID: 19153243
- Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A: Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009 Jan 16; 2009 Jan 12. PMID: 19139171
- Tal MC, Iwasaki A: Autophagy and innate recognition systems. Curr Top Microbiol Immunol. 2009. PMID: 19802562
- Iijima N, Iwasaki A: [Mucosal immune defense against sexually transmitted diseases]. Nihon Rinsho. 2009 Jan. PMID: 19177745
- Iijima N, Linehan MM, Zamora M, Butkus D, Dunn R, Kehry MR, Laufer TM, Iwasaki A: Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J Exp Med. 2008 Dec 22; 2008 Dec 1. PMID: 19047439
- Ichinohe T, Iwasaki A, Hasegawa H: Innate sensors of influenza virus: clues to developing better intranasal vaccines. Expert Rev Vaccines. 2008 Nov. PMID: 18980544
- Thompson JM, Iwasaki A: Toll-like receptors regulation of viral infection and disease. Adv Drug Deliv Rev. 2008 Apr 29; 2007 Dec 28. PMID: 18280610
- Lee HK, Iwasaki A: Autophagy and antiviral immunity. Curr Opin Immunol. 2008 Feb; 2008 Feb 8. PMID: 18262399
- Iijima N, Linehan MM, Saeland S, Iwasaki A: Vaginal epithelial dendritic cells renew from bone marrow precursors. Proc Natl Acad Sci U S A. 2007 Nov 27; 2007 Nov 15. PMID: 18006657
- Iwasaki A: Role of autophagy in innate viral recognition. Autophagy. 2007 Jul-Aug; 2007 Jul 7. PMID: 17404496
- Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A: Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007 Mar 9; 2007 Feb 1. PMID: 17272685
- Iwasaki A: Division of labor by dendritic cells. Cell. 2007 Feb 9. PMID: 17289563
- Lee HK, Iwasaki A: Innate control of adaptive immunity: dendritic cells and beyond. Semin Immunol. 2007 Feb; 2007 Feb 5. PMID: 17276695
- Iwasaki A: Mucosal dendritic cells. Annu Rev Immunol. 2007. PMID: 17378762
- Lund JM, Linehan MM, Iijima N, Iwasaki A: Cutting Edge: Plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J Immunol. 2006 Dec 1. PMID: 17114418
- Sato A, Linehan MM, Iwasaki A: Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A. 2006 Nov 14; 2006 Nov 3. PMID: 17085599
- Shen H, Iwasaki A: A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide. J Clin Invest. 2006 Aug; 2006 Jul 27. PMID: 16878177
- Iwasaki A: The use of bone marrow-chimeric mice in elucidating immune mechanisms. Methods Mol Med. 2006. PMID: 16988461
- Soderberg KA, Payne GW, Sato A, Medzhitov R, Segal SS, Iwasaki A: Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proc Natl Acad Sci U S A. 2005 Nov 8; 2005 Oct 31. PMID: 16260739
- Fleeton M, Contractor N, Leon F, He J, Wetzel D, Dermody T, Iwasaki A, Kelsall B: Involvement of dendritic cell subsets in the induction of oral tolerance and immunity. Ann N Y Acad Sci. 2004 Dec. PMID: 15681744
- Sato A, Iwasaki A: Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments. Proc Natl Acad Sci U S A. 2004 Nov 16; 2004 Nov 8. PMID: 15534227
- Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004 Oct. PMID: 15454922
- Soderberg KA, Linehan MM, Ruddle NH, Iwasaki A: MAdCAM-1 expressing sacral lymph node in the lymphotoxin beta-deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection. J Immunol. 2004 Aug 1. PMID: 15265924
- 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. Proc Natl Acad Sci U S A. 2004 Apr 13; 2004 Mar 19. PMID: 15034168
- 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. J Virol. 2004 Mar. PMID: 14963155
- Iwasaki A: The role of dendritic cells in immune responses against vaginal infection by herpes simplex virus type 2. Microbes Infect. 2003 Nov. PMID: 14623018
- 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. J Immunol. 2003 Sep 15. PMID: 12960300
- 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. J Exp Med. 2003 Aug 4. PMID: 12900525
- Iwasaki A: The importance of CD11b+ dendritic cells in CD4+ T cell activation in vivo: with help from interleukin 1. J Exp Med. 2003 Jul 21; 2003 Jul 14. PMID: 12860934
- 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. J Exp Med. 2003 Jan 20. PMID: 12538655
- Iwasaki A, Welker R, Mueller S, Linehan M, Nomoto A, Wimmer E: Immunofluorescence analysis of poliovirus receptor expression in Peyer's patches of humans, primates, and CD155 transgenic mice: implications for poliovirus infection. J Infect Dis. 2002 Sep 1; 2002 Aug 9. PMID: 12195344
- Jameson B, Baribaud F, Pöhlmann S, Ghavimi D, Mortari F, Doms RW, Iwasaki A: Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J Virol. 2002 Feb. PMID: 11799181