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  • 1
    Publication Date: 2011-02-26
    Description: Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for 〉1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057367/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057367/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kasturi, Sudhir Pai -- Skountzou, Ioanna -- Albrecht, Randy A -- Koutsonanos, Dimitrios -- Hua, Tang -- Nakaya, Helder I -- Ravindran, Rajesh -- Stewart, Shelley -- Alam, Munir -- Kwissa, Marcin -- Villinger, Francois -- Murthy, Niren -- Steel, John -- Jacob, Joshy -- Hogan, Robert J -- Garcia-Sastre, Adolfo -- Compans, Richard -- Pulendran, Bali -- HHSN266200700006C/PHS HHS/ -- HHSN266200700010C/PHS HHS/ -- N01 AI50025/AI/NIAID NIH HHS/ -- R01 AI048638/AI/NIAID NIH HHS/ -- R01 AI048638-07/AI/NIAID NIH HHS/ -- R01 AI048638-08/AI/NIAID NIH HHS/ -- R01 DK057665/DK/NIDDK NIH HHS/ -- R01 DK057665-09/DK/NIDDK NIH HHS/ -- R01 DK057665-10/DK/NIDDK NIH HHS/ -- R01 DK057665-11/DK/NIDDK NIH HHS/ -- R01 DK057665-12/DK/NIDDK NIH HHS/ -- R01 DK057665-13/DK/NIDDK NIH HHS/ -- R01DK057665/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 AI048638-09A1/AI/NIAID NIH HHS/ -- R37 AI048638-10/AI/NIAID NIH HHS/ -- R37 AI048638-11/AI/NIAID NIH HHS/ -- R37AI48638/AI/NIAID NIH HHS/ -- R56 AI048638/AI/NIAID NIH HHS/ -- R56 AI048638-09/AI/NIAID NIH HHS/ -- U01AI070469/AI/NIAID NIH HHS/ -- U19AI057266/AI/NIAID NIH HHS/ -- U19AI090023/AI/NIAID NIH HHS/ -- U54AI057157/AI/NIAID NIH HHS/ -- U54AI57158/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Feb 24;470(7335):543-7. doi: 10.1038/nature09737.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350488" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/biosynthesis/*immunology ; Antibodies, Viral/biosynthesis/*immunology ; Antibody Formation/*immunology ; Dendritic Cells/cytology/immunology ; Hemagglutinin Glycoproteins, Influenza Virus/immunology ; Immunity, Innate/*immunology ; Immunologic Memory/*immunology ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H5N1 Subtype/immunology ; Influenza Vaccines/administration & dosage/*immunology ; Lactic Acid ; Ligands ; Lymph Nodes/cytology/immunology ; Lymphocyte Activation ; Macaca mulatta/immunology/virology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Nanoparticles/administration & dosage ; Plasma Cells/cytology/immunology/metabolism ; Polyglycolic Acid ; T-Lymphocytes/immunology ; Toll-Like Receptors/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-03-17
    Description: The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1beta resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Loebbermann, Jens -- Nakaya, Helder I -- Khan, Nooruddin -- Ma, Hualing -- Gama, Leonardo -- Machiah, Deepa K -- Lawson, Benton -- Hakimpour, Paul -- Wang, Yi-chong -- Li, Shuzhao -- Sharma, Prachi -- Kaufman, Randal J -- Martinez, Jennifer -- Pulendran, Bali -- R01 DK088227/DK/NIDDK NIH HHS/ -- R01 DK103185/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK042394/DK/NIDDK NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- ZIA ES103286-01/Intramural NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):523-7. doi: 10.1038/nature17186. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508, Brazil. ; Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India. ; Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Virology Core, Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Degenerative Disease Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037 USA. ; National Institute of Environmental Health Sciences, Mail Drop D2-01 Research Triangle Park, North Carolina 27709, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982722" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/administration & dosage/deficiency/*metabolism/pharmacology ; Animals ; Antigen-Presenting Cells/immunology/metabolism ; Autophagy ; Colitis/etiology/*metabolism/pathology/prevention & control ; Disease Models, Animal ; Epithelial Cells/metabolism ; Female ; Humans ; Inflammasomes/*antagonists & inhibitors/metabolism ; Inflammation/etiology/*metabolism/pathology/prevention & control ; Interleukin-1beta/immunology ; Intestines/*metabolism/*pathology ; Male ; Mice ; Microtubule-Associated Proteins/deficiency/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; Th17 Cells/immunology ; Ubiquitin-Activating Enzymes/deficiency/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-12-07
    Description: The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Khan, Nooruddin -- Nakaya, Helder I -- Li, Shuzhao -- Loebbermann, Jens -- Maddur, Mohan S -- Park, Youngja -- Jones, Dean P -- Chappert, Pascal -- Davoust, Jean -- Weiss, David S -- Virgin, Herbert W -- Ron, David -- Pulendran, Bali -- 084812/Wellcome Trust/United Kingdom -- 084812/Z/08/Z/Wellcome Trust/United Kingdom -- N01 AI50019/AI/NIAID NIH HHS/ -- N01 AI50025/AI/NIAID NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- R56 AI048638/AI/NIAID NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):313-7. doi: 10.1126/science.1246829. Epub 2013 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24310610" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antigen Presentation ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line ; Cricetinae ; Dendritic Cells/enzymology/*immunology ; Enzyme Activation ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microtubule-Associated Proteins/genetics ; Protein-Serine-Threonine Kinases/*biosynthesis/genetics ; Yellow Fever Vaccine/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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