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Article ; Online: Use of hepadnavirus core proteins as vaccine platforms.

Whitacre, David C / Lee, Byung O / Milich, David R

2009 Volume 8, Issue 11, Page(s) 1565–1573

Abstract: The first virus-like particle to be tested for use as a vaccine carrier was based on the hepatitis B virus nucleocapsid protein. This viral subunit, while not infectious on its own, is a 36-nm particle that is highly immunogenic during a natural ... ...

Abstract	The first virus-like particle to be tested for use as a vaccine carrier was based on the hepatitis B virus nucleocapsid protein. This viral subunit, while not infectious on its own, is a 36-nm particle that is highly immunogenic during a natural infection. The self-assembly and high degree of immunogenicity is maintained when expressed as a recombinant protein and, moreover, can confer a high degree of immunogenicity on foreign antigens linked to the particle, either chemically or genetically. This review describes the current state of the hepadnaviral core protein as a vaccine carrier.
MeSH term(s)	Carrier Proteins/genetics ; Carrier Proteins/immunology ; Hepatitis B Core Antigens/genetics ; Hepatitis B Core Antigens/immunology ; Hepatitis B virus/genetics ; Humans ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Vaccines, Synthetic/genetics ; Vaccines, Virosome/genetics ; Vaccines, Virosome/immunology
Chemical Substances	Carrier Proteins ; Hepatitis B Core Antigens ; Recombinant Fusion Proteins ; Vaccines, Synthetic ; Vaccines, Virosome
Language	English
Publishing date	2009-10-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2181284-6
ISSN	1744-8395 ; 1476-0584
ISSN (online)	1744-8395
ISSN	1476-0584
DOI	10.1586/erv.09.121
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Article ; Online: Species-Specific Structural Requirements of Alpha-Branched Trehalose Diester Mincle Agonists.

Smith, Alyson J / Miller, Shannon M / Buhl, Cassandra / Child, Robert / Whitacre, Margaret / Schoener, Roman / Ettenger, George / Burkhart, David / Ryter, Kendal / Evans, Jay T

Frontiers in immunology

2019 Volume 10, Page(s) 338

Abstract: Despite the ever present need for an ... ...

Abstract	Despite the ever present need for an effective
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Cell Line ; Cord Factors/chemistry ; Cord Factors/immunology ; Cytokines/metabolism ; Humans ; Immunity, Cellular ; Lectins, C-Type ; Mice ; Molecular Structure ; Mycobacterium tuberculosis/immunology ; Structure-Activity Relationship ; Th17 Cells/immunology ; Th17 Cells/metabolism ; Trehalose/chemistry ; Trehalose/immunology
Chemical Substances	Adjuvants, Immunologic ; Cord Factors ; Cytokines ; Lectins, C-Type ; Trehalose (B8WCK70T7I)
Language	English
Publishing date	2019-02-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00338
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Article ; Online: P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.

Whitacre, David C / Espinosa, Diego A / Peters, Cory J / Jones, Joyce E / Tucker, Amy E / Peterson, Darrell L / Zavala, Fidel P / Milich, David R

PloS one

2015 Volume 10, Issue 5, Page(s) e0124856

Abstract: In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of ... ...

Abstract	In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x10(6)) and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.
MeSH term(s)	Animals ; Antibodies, Protozoan/immunology ; CD4-Positive T-Lymphocytes/immunology ; Epitopes, B-Lymphocyte/chemistry ; Epitopes, B-Lymphocyte/immunology ; Epitopes, T-Lymphocyte/chemistry ; Epitopes, T-Lymphocyte/immunology ; Hepatitis B Virus, Woodchuck/immunology ; Immunity ; Immunization ; Life Cycle Stages ; Malaria, Falciparum/immunology ; Malaria, Falciparum/parasitology ; Malaria, Falciparum/prevention & control ; Malaria, Vivax/immunology ; Malaria, Vivax/parasitology ; Malaria, Vivax/prevention & control ; Mice, Inbred C57BL ; Plasmodium falciparum/immunology ; Plasmodium vivax/immunology ; Protozoan Proteins/immunology ; Rabbits ; Repetitive Sequences, Amino Acid ; Reproducibility of Results ; Virion/immunology
Chemical Substances	Antibodies, Protozoan ; Epitopes, B-Lymphocyte ; Epitopes, T-Lymphocyte ; Protozoan Proteins ; circumsporozoite protein, Protozoan
Language	English
Publishing date	2015-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0124856
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Article ; Online: Novel Lipidated Imidazoquinoline TLR7/8 Adjuvants Elicit Influenza-Specific Th1 Immune Responses and Protect Against Heterologous H3N2 Influenza Challenge in Mice.

Miller, Shannon M / Cybulski, Van / Whitacre, Margaret / Bess, Laura S / Livesay, Mark T / Walsh, Lois / Burkhart, David / Bazin, Hélène G / Evans, Jay T

Frontiers in immunology

2020 Volume 11, Page(s) 406

Abstract: Most licensed seasonal influenza vaccines are non-adjuvanted and rely primarily on vaccine-induced antibody titers for protection. As such, seasonal antigenic drift and suboptimal vaccine strain selection often results in reduced vaccine efficacy. ... ...

Abstract	Most licensed seasonal influenza vaccines are non-adjuvanted and rely primarily on vaccine-induced antibody titers for protection. As such, seasonal antigenic drift and suboptimal vaccine strain selection often results in reduced vaccine efficacy. Further, seasonal H3N2 influenza vaccines demonstrate poor efficacy compared to H1N1 and influenza type B vaccines. New vaccines, adjuvants, or delivery technologies that can induce broader or cross-seasonal protection against drifted influenza virus strains, likely through induction of protective T cell responses, are urgently needed. Here, we report novel lipidated TLR7/8 ligands that act as strong adjuvants to promote influenza-virus specific Th1-and Th17-polarized T cell responses and humoral responses in mice with no observable toxicity. Further, the adjuvanted influenza vaccine provided protection against a heterologous H3N2 influenza challenge in mice. These responses were further enhanced when combined with a synthetic TLR4 ligand adjuvant. Despite differences between human and mouse TLR7/8, these novel lipidated imidazoquinolines induced the production of cytokines required to polarize a Th1 and Th17 immune response in human PBMCs providing additional support for further development of these compounds as novel adjuvants for the induction of broad supra-seasonal protection from influenza virus.
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Cross Reactions ; Disease Models, Animal ; Female ; HEK293 Cells ; Humans ; Imidazoles/chemical synthesis ; Imidazoles/immunology ; Immunity, Heterologous ; Immunity, Humoral ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza A Virus, H3N2 Subtype/physiology ; Influenza B virus/physiology ; Influenza Vaccines/immunology ; Influenza, Human/immunology ; Lipids/chemical synthesis ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/immunology ; Quinolines/chemical synthesis ; Quinolines/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Toll-Like Receptor 7/agonists ; Toll-Like Receptor 8/agonists
Chemical Substances	Adjuvants, Immunologic ; Imidazoles ; Influenza Vaccines ; Lipids ; Quinolines ; TLR7 protein, human ; TLR8 protein, human ; Toll-Like Receptor 7 ; Toll-Like Receptor 8 ; imidazo(4,5-g)quinoline
Language	English
Publishing date	2020-03-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.00406
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Article ; Online: Palivizumab epitope-displaying virus-like particles protect rodents from RSV challenge.

Schickli, Jeanne H / Whitacre, David C / Tang, Roderick S / Kaur, Jasmine / Lawlor, Heather / Peters, Cory J / Jones, Joyce E / Peterson, Darrell L / McCarthy, Michael P / Van Nest, Gary / Milich, David R

The Journal of clinical investigation

2015 Volume 125, Issue 4, Page(s) 1637–1647

Abstract: Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the ...

Abstract	Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the incidence of RSV disease in premature or at-risk infants. The palivizumab epitope is a well-characterized, approximately 24-aa helix-loop-helix structure on the RSV fusion (F) protein (F254-277). Here, we genetically inserted this epitope and multiple site variants of this epitope within a versatile woodchuck hepadnavirus core-based virus-like particle (WHcAg-VLP) to generate hybrid VLPs that each bears 240 copies of the RSV epitope in a highly immunogenic arrayed format. A challenge of such an epitope-focused approach is that to be effective, the conformational F254-277 epitope must elicit antibodies that recognize the intact virus. A number of hybrid VLPs containing RSV F254-277 were recognized by palivizumab in vitro and elicited high-titer and protective neutralizing antibody in rodents. Together, the results from this proof-of-principle study suggest that the WHcAg-VLP technology may be an applicable approach to eliciting a response to other structural epitopes.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Viral/biosynthesis ; Antibodies, Viral/immunology ; Antibody Specificity ; Antigens, Viral/immunology ; Combinatorial Chemistry Techniques ; Cryoelectron Microscopy ; Enzyme-Linked Immunosorbent Assay ; Helix-Loop-Helix Motifs/immunology ; Hepatitis B Virus, Woodchuck/genetics ; Humans ; Immunodominant Epitopes/immunology ; Immunoglobulin G/biosynthesis ; Immunoglobulin G/immunology ; Mice ; Mice, Inbred BALB C ; Palivizumab ; Protein Conformation ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/immunology ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Viruses/immunology ; Sigmodontinae ; Vaccination ; Vaccines, Virus-Like Particle ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/immunology ; Viral Vaccines/immunology
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antibodies, Viral ; Antigens, Viral ; F protein, human respiratory syncytial virus ; Immunodominant Epitopes ; Immunoglobulin G ; Recombinant Fusion Proteins ; Vaccines, Virus-Like Particle ; Viral Fusion Proteins ; Viral Vaccines ; Palivizumab (DQ448MW7KS)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI78450
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Article ; Online: P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.

David C Whitacre / Diego A Espinosa / Cory J Peters / Joyce E Jones / Amy E Tucker / Darrell L Peterson / Fidel P Zavala / David R Milich

PLoS ONE, Vol 10, Iss 5, p e

2015 Volume 0124856

Abstract	In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x10(6)) and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Evaluation of a proposal for reliable low-cost grid power with 100% wind, water, and solar.

Proceedings of the National Academy of Sciences of the United States of America

2017 Volume 114, Issue 26, Page(s) 6722–6727

Abstract: A number of analyses, meta-analyses, and assessments, including those performed by the Intergovernmental Panel on Climate Change, the National Oceanic and Atmospheric Administration, the National Renewable Energy Laboratory, and the International Energy ... ...

Abstract	A number of analyses, meta-analyses, and assessments, including those performed by the Intergovernmental Panel on Climate Change, the National Oceanic and Atmospheric Administration, the National Renewable Energy Laboratory, and the International Energy Agency, have concluded that deployment of a diverse portfolio of clean energy technologies makes a transition to a low-carbon-emission energy system both more feasible and less costly than other pathways. In contrast, Jacobson et al. [Jacobson MZ, Delucchi MA, Cameron MA, Frew BA (2015) Proc Natl Acad Sci USA 112(49):15060-15065] argue that it is feasible to provide "low-cost solutions to the grid reliability problem with 100% penetration of WWS [wind, water and solar power] across all energy sectors in the continental United States between 2050 and 2055", with only electricity and hydrogen as energy carriers. In this paper, we evaluate that study and find significant shortcomings in the analysis. In particular, we point out that this work used invalid modeling tools, contained modeling errors, and made implausible and inadequately supported assumptions. Policy makers should treat with caution any visions of a rapid, reliable, and low-cost transition to entire energy systems that relies almost exclusively on wind, solar, and hydroelectric power.
Language	English
Publishing date	2017-06-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1610381114
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Article ; Online: Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation.

Cox, Gina Mavrikis / Kithcart, Aaron P / Pitt, David / Guan, Zhen / Alexander, Jessica / Williams, Jessica L / Shawler, Todd / Dagia, Nilesh M / Popovich, Phillip G / Satoskar, Abhay R / Whitacre, Caroline C

Journal of immunology (Baltimore, Md. : 1950)

2013 Volume 191, Issue 3, Page(s) 1043–1054

Abstract: ... 1β, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C ...

Abstract	Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF-deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1β, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-β, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS.
MeSH term(s)	Adult ; Aged ; Animals ; CCAAT-Enhancer-Binding Protein-beta/biosynthesis ; Central Nervous System/immunology ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Female ; Humans ; Inflammation/immunology ; Interleukin-1beta/biosynthesis ; Interleukin-6/biosynthesis ; Intramolecular Oxidoreductases/deficiency ; Intramolecular Oxidoreductases/genetics ; Intramolecular Oxidoreductases/physiology ; Macrophage Migration-Inhibitory Factors/deficiency ; Macrophage Migration-Inhibitory Factors/genetics ; Macrophage Migration-Inhibitory Factors/physiology ; Macrophages/immunology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/metabolism ; Multiple Sclerosis/metabolism ; Nitric Oxide Synthase Type II/biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis
Chemical Substances	CCAAT-Enhancer-Binding Protein-beta ; Interleukin-1beta ; Interleukin-6 ; Macrophage Migration-Inhibitory Factors ; Tumor Necrosis Factor-alpha ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39) ; Intramolecular Oxidoreductases (EC 5.3.-) ; Mif protein, mouse (EC 5.3.2.1)
Language	English
Publishing date	2013-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1200485
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Article: Androgen induction of in vitro prostate cell differentiation.

Whitacre, David C / Chauhan, Sanjay / Davis, Tracy / Gordon, Debra / Cress, Anne E / Miesfeld, Roger L

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

2002 Volume 13, Issue 1, Page(s) 1–11

Abstract: ... of the mitochondrial aspartate aminotransferase or c-Myc genes by Northern blot analysis, RNA expression profiling of DHT-treated CA25 cells ...

Abstract	To better understand androgen action in normal prostate cells, we characterized the androgen growth response of an immortalized nontumorigenic rat prostate cell line called CA25 that had been stably transfected with androgen receptor (AR) cDNA. Surprisingly, we found that AR(+) CA25 cells grew slower in the presence of dihydrotestosterone (DHT), whereas the growth of AR(-) CA25 cells was not affected by the hormone. DHT-mediated growth inhibition of CA25 cells was not attributable to an increase in apoptosis but rather to a morphological conversion consistent with terminal differentiation. Specifically, we found that DHT treatment of CA25 cells resulted in a striking change in cell architecture, localization of desmoplakin to cell-cell boundaries, and an increase in alpha 6p integrin levels, a newly described marker of cell differentiation. Although no androgen-dependent changes were observed in the transcript levels of the mitochondrial aspartate aminotransferase or c-Myc genes by Northern blot analysis, RNA expression profiling of DHT-treated CA25 cells identified 282 genes of 1,018 that were continually expressed over a 48-h period. It was found that 63 of these genes were up-regulated >5-fold within the first 4 h of treatment and encoded functions involved in transport, signal transduction, and metabolism. These expression profile data are consistent with the striking morphological changes we observed in DHT-treated CA25 cells and provide a starting point for molecular analysis of in vitro prostate cell differentiation.
MeSH term(s)	Animals ; Antigens, CD/biosynthesis ; Cell Differentiation/drug effects ; Cell Division/drug effects ; Cell Line, Transformed ; Dihydrotestosterone/pharmacology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Integrin alpha6 ; Male ; Mammary Tumor Virus, Mouse/genetics ; Prostate/cytology ; Prostate/metabolism ; Rats ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Transcription, Genetic/drug effects ; Transfection ; Up-Regulation
Chemical Substances	Antigens, CD ; Integrin alpha6 ; Receptors, Androgen ; Dihydrotestosterone (08J2K08A3Y)
Language	English
Publishing date	2002-01
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1034269-2
ISSN	1044-9523
ISSN	1044-9523
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Zs.A 2903: Show issues

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Article ; Online: Interaction of the hepatitis B core antigen and the innate immune system.

Lee, Byung O / Tucker, Amy / Frelin, Lars / Sallberg, Matti / Jones, Joyce / Peters, Cory / Hughes, Janice / Whitacre, David / Darsow, Bryan / Peterson, Darrell L / Milich, David R

Journal of immunology (Baltimore, Md. : 1950)

2009 Volume 182, Issue 11, Page(s) 6670–6681

Abstract: Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells (DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4(+) T cells than splenic B2 ...

Abstract	Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells (DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4(+) T cells than splenic B2 cells. This was demonstrated by direct HBcAg-biotin-binding studies and by HBcAg-specific T cell activation in vitro in cultures of naive HBcAg-specific T cells and resting B cell subpopulations. The inability of DC to function as APCs for exogenous HBcAg relates to lack of uptake of HBcAg, not to processing or presentation, because HBcAg/anti-HBc immune complexes can be efficiently presented by DC. Furthermore, HBcAg-specific CD4(+) and CD8(+) T cell priming with DNA encoding HBcAg does not require B cell APCs. TLR activation, another innate immune response, was also examined. Full-length (HBcAg(183)), truncated (HBcAg(149)), and the nonparticulate HBeAg were screened for TLR stimulation via NF-kappaB activation in HEK293 cells expressing human TLRs. None of the HBc/HBeAgs activated human TLRs. Therefore, the HBc/HBeAg proteins are not ligands for human TLRs. However, the ssRNA contained within HBcAg(183) does function as a TLR-7 ligand, as demonstrated at the T and B cell levels in TLR-7 knockout mice. Bacterial, yeast, and mammalian ssRNA encapsidated within HBcAg(183) all function as TLR-7 ligands. These studies indicate that innate immune mechanisms bridge to and enhance the adaptive immune response to HBcAg and have important implications for the use of hepadnavirus core proteins as vaccine carrier platforms.
MeSH term(s)	Animals ; Antigen-Presenting Cells/immunology ; B-Lymphocytes/classification ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Line ; Hepatitis B Core Antigens/immunology ; Humans ; Immunity, Innate/immunology ; Lymphocyte Activation ; Male ; Membrane Glycoproteins/immunology ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Knockout ; NF-kappa B/metabolism ; RNA, Viral/metabolism ; Spleen/cytology ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 7/metabolism
Chemical Substances	Hepatitis B Core Antigens ; Membrane Glycoproteins ; NF-kappa B ; RNA, Viral ; Tlr7 protein, mouse ; Toll-Like Receptor 7
Language	English
Publishing date	2009-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0803683
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 28: Show issues

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