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  1. Article ; Online: Robust gene expression changes in the ganglia following subclinical reactivation in rhesus macaques infected with simian varicella virus.

    Arnold, Nicole / Meyer, Christine / Engelmann, Flora / Messaoudi, Ilhem

    Journal of neurovirology

    2017  Volume 23, Issue 4, Page(s) 520–538

    Abstract: Varicella zoster virus (VZV) causes varicella during acute infection and establishes latency in the sensory ganglia. Reactivation of VZV results in herpes zoster, a debilitating and painful disease. It is believed that VZV reactivates due to a decline in ...

    Abstract Varicella zoster virus (VZV) causes varicella during acute infection and establishes latency in the sensory ganglia. Reactivation of VZV results in herpes zoster, a debilitating and painful disease. It is believed that VZV reactivates due to a decline in cell-mediated immunity; however, the roles that CD4 versus CD8 T cells play in the prevention of herpes zoster remain poorly understood. To address this question, we used a well-characterized model of VZV infection where rhesus macaques are intrabronchially infected with the homologous simian varicella virus (SVV). Latently infected rhesus macaques were thymectomized and depleted of either CD4 or CD8 T cells to induce selective senescence of each T cell subset. After T cell depletion, the animals were transferred to a new housing room to induce stress. SVV reactivation (viremia in the absence of rash) was detected in three out of six CD8-depleted and two out of six CD4-depleted animals suggesting that both CD4 and CD8 T cells play a critical role in preventing SVV reactivation. Viral loads in multiple ganglia were higher in reactivated animals compared to non-reactivated animals. In addition, reactivation results in sustained transcriptional changes in the ganglia that enriched to gene ontology and diseases terms associated with neuronal function and inflammation indicative of potential damage as a result of viral reactivation. These studies support the critical role of cellular immunity in preventing varicella virus reactivation and indicate that reactivation results in long-lasting remodeling of the ganglia transcriptome.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/virology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/virology ; Female ; Ganglia, Sensory/immunology ; Ganglia, Sensory/virology ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Ontology ; Herpes Zoster/genetics ; Herpes Zoster/immunology ; Herpes Zoster/veterinary ; Herpesvirus 3, Human/immunology ; Lymphocyte Depletion/methods ; Macaca mulatta ; Male ; Molecular Sequence Annotation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/immunology ; Stress, Psychological ; Thymectomy ; Thymus Gland/immunology ; Thymus Gland/surgery ; Thymus Gland/virology ; Virus Activation/immunology
    Chemical Substances Nerve Tissue Proteins
    Language English
    Publishing date 2017-03-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1283265-0
    ISSN 1538-2443 ; 1355-0284
    ISSN (online) 1538-2443
    ISSN 1355-0284
    DOI 10.1007/s13365-017-0522-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: microRNAs Regulate Host Immune Response and Pathogenesis During Influenza Infection in Rhesus Macaques.

    Rivera, Andrea / Barr, Tasha / Rais, Maham / Engelmann, Flora / Messaoudi, Ilhem

    Viral immunology

    2016  Volume 29, Issue 4, Page(s) 212–227

    Abstract: microRNAs (miRNAs) are small noncoding RNAs that are key regulators of biological processes, including the immune response to viral infections. Differential expression levels of cellular miRNAs and their predicted targets have been described in the lungs ...

    Abstract microRNAs (miRNAs) are small noncoding RNAs that are key regulators of biological processes, including the immune response to viral infections. Differential expression levels of cellular miRNAs and their predicted targets have been described in the lungs of H1N1-infected BALB/c mice, the lungs of H5N1 influenza-infected cynomolgus macaques, and in peripheral blood mononuclear cells (PBMCs) of critically ill patients infected with 2009 pandemic H1N1. However, a longitudinal analysis of changes in the expression of miRNAs and their targets during influenza infection and how they relate to viral replication and host response has yet to be carried out. In the present study, we conducted a comprehensive analysis of innate and adaptive immune responses as well as the expression of several miRNAs and their validated targets in both peripheral blood and bronchoalveolar lavage (BAL) collected from rhesus macaques over the course of infection with the 2009 H1N1 virus A/Mexico/4108/2009 (MEX4108). We describe a distinct set of differentially expressed miRNAs in BAL and PBMCs, which regulate the expression of genes involved in inflammation, immune response, and regulation of cell cycle and apoptosis.
    Language English
    Publishing date 2016-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639075-4
    ISSN 1557-8976 ; 0882-8245
    ISSN (online) 1557-8976
    ISSN 0882-8245
    DOI 10.1089/vim.2015.0074
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Protection Against Marburg Virus Using a Recombinant VSV-Vaccine Depends on T and B Cell Activation.

    Marzi, Andrea / Menicucci, Andrea R / Engelmann, Flora / Callison, Julie / Horne, Eva J / Feldmann, Friederike / Jankeel, Allen / Feldmann, Heinz / Messaoudi, Ilhem

    Frontiers in immunology

    2019  Volume 9, Page(s) 3071

    Abstract: Marburg virus (MARV) is the causative agent of hemorrhagic fever outbreaks with high case fatality rates. Closely related to Ebola virus, MARV is a filamentous virus with a negative-sense, single-stranded RNA genome. Although extensive studies on ... ...

    Abstract Marburg virus (MARV) is the causative agent of hemorrhagic fever outbreaks with high case fatality rates. Closely related to Ebola virus, MARV is a filamentous virus with a negative-sense, single-stranded RNA genome. Although extensive studies on filovirus countermeasures have been conducted, there are no licensed treatments against MARV infections. An experimental vaccine based on the recombinant vesicular stomatitis virus (VSV) expressing the MARV-Musoke glycoprotein demonstrated complete protection when a single dose was administered 28 days and up to 14 months prior to MARV challenge. Here, we analyzed the protective efficacy of an updated vaccine expressing the MARV-Angola glycoprotein (VSV-MARV). A single dose of VSV-MARV given 5 weeks before challenge provided uniform protection with no detectable viremia. The vaccine induced B and T cell proliferation and, importantly, antigen-specific IgG production. Transcriptomic signatures confirm these findings and suggest innate immunity engendered by VSV-MARV may direct the development of protective humoral immunity.
    MeSH term(s) Animals ; B-Lymphocytes/immunology ; Disease Models, Animal ; Female ; Humans ; Lymphocyte Activation ; Macaca fascicularis ; Male ; Marburg Virus Disease/immunology ; Marburg Virus Disease/prevention & control ; Marburg Virus Disease/virology ; Marburgvirus/immunology ; T-Lymphocytes/immunology ; Treatment Outcome ; Vaccines, Synthetic/administration & dosage ; Vaccines, Synthetic/immunology ; Vesiculovirus/immunology ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/immunology ; Viral Vaccines/administration & dosage ; Viral Vaccines/immunology ; Viremia/immunology ; Viremia/prevention & control ; Viremia/virology
    Chemical Substances GP-protein, Marburg virus ; Vaccines, Synthetic ; Viral Envelope Proteins ; Viral Vaccines
    Language English
    Publishing date 2019-01-22
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.03071
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women.

    Engelmann, Flora / Rivera, Andrea / Park, Byung / Messerle-Forbes, Marci / Jensen, Jeffrey T / Messaoudi, Ilhem

    PloS one

    2016  Volume 11, Issue 2, Page(s) e0149045

    Abstract: It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the ... ...

    Abstract It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the age-related decline in immune function, known as immune senescence. Therefore, in this study, we determined the impact of menopause and estrogen therapy (ET) on lymphocyte subset frequency as well as the immune response to seasonal influenza vaccine in three different groups: 1) young adult women (regular menstrual cycles, not on hormonal contraception); 2) post-menopausal (at least 2 years) women who are not receiving any form of hormone therapy (HT) and 3) post-menopausal hysterectomized women receiving ET. Although the numbers of circulating CD4 and CD20 B cells were reduced in the post-menopausal group receiving ET, we also detected a better preservation of naïve B cells, decreased CD4 T cell inflammatory cytokine production, and slightly lower circulating levels of the pro-inflammatory cytokine IL-6. Following vaccination, young adult women generated more robust antibody and T cell responses than both post-menopausal groups. Despite similar vaccine responses between the two post-menopausal groups, we observed a direct correlation between plasma 17β estradiol (E2) levels and fold increase in IgG titers within the ET group. These findings suggest that ET affects immune homeostasis and that higher plasma E2 levels may enhance humoral responses in post-menopausal women.
    MeSH term(s) Antibody Formation/drug effects ; CD4 Lymphocyte Count ; Enzyme-Linked Immunosorbent Assay ; Estradiol/blood ; Estrogen Replacement Therapy/adverse effects ; Female ; Homeostasis/drug effects ; Homeostasis/physiology ; Humans ; Influenza Vaccines/immunology ; Interleukins/blood ; Lymphocyte Count ; Lymphocytes/drug effects ; Lymphocytes/physiology ; Menopause/drug effects ; Menopause/immunology ; Menopause/physiology ; Middle Aged ; Progesterone/blood
    Chemical Substances Influenza Vaccines ; Interleukins ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E)
    Language English
    Publishing date 2016-02-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0149045
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Intrabronchial infection of rhesus macaques with simian varicella virus results in a robust immune response in the lungs.

    Haberthur, Kristen / Meyer, Christine / Arnold, Nicole / Engelmann, Flora / Jeske, Daniel R / Messaoudi, Ilhem

    Journal of virology

    2014  Volume 88, Issue 21, Page(s) 12777–12792

    Abstract: Unlabelled: Varicella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella ... ...

    Abstract Unlabelled: Varicella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella lesions or by direct contact with infectious vesicular fluid. However, the ensuing immune response in the lungs remains incompletely understood. We have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we performed an in-depth analysis of the host immune response to acute SVV infection in the lungs and peripheral blood. We report that acute SVV infection results in a robust innate immune response in the lungs, characterized by the production of inflammatory cytokines, chemokines, and growth factors as well as an increased frequency of plasmacytoid dendritic cells (DCs) that corresponded with alpha interferon (IFN-α) production and a rapid decrease in viral loads in the lungs. This is followed by T and B cell proliferation, antibody production, T cell differentiation, and cytokine production, which correlate with the complete cessation of viral replication. Although terminally differentiated CD8 T cells became the predominant T cell population in bronchoalveolar lavage cells, a higher percentage of CD4 T cells were SVV specific, which suggests a critical role for these cells in the resolution of primary SVV infection in the lungs. Given the homology between SVV and VZV, our data provide insight into the immune response to VZV within the lung.
    Importance: Although primary VZV infection occurs primarily via the respiratory route, the host response in the lungs and its contribution to the cessation of viral replication and establishment of latency remain poorly understood. The difficulty in accessing lung tissue and washes from individuals infected with VZV has hampered efforts to address this knowledge gap. SVV infection of rhesus macaques is an important model of VZV infection of humans; therefore, we utilized this animal model to gain a comprehensive view of the kinetics of the immune response to SVV in the lung and its relationship to the resolution of acute infection in respiratory tissues. These data not only advance our understanding of host immunity to VZV, a critical step in developing new vaccines, but also provide additional insight into immunity to respiratory pathogens.
    MeSH term(s) Animals ; Cytokines/metabolism ; Dendritic Cells/immunology ; Disease Models, Animal ; Female ; Herpesviridae Infections/immunology ; Herpesviridae Infections/pathology ; Herpesviridae Infections/virology ; Lung/immunology ; Lung/pathology ; Lung/virology ; Macaca mulatta ; Male ; T-Lymphocytes/immunology ; Varicellovirus/immunology ; Viral Load
    Chemical Substances Cytokines
    Keywords covid19
    Language English
    Publishing date 2014-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.01814-14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A novel murine model of differentiation-mediated cytomegalovirus reactivation from latently infected bone marrow haematopoietic cells.

    Liu, Xue-Feng / Swaminathan, Suchitra / Yan, Shixian / Engelmann, Flora / Abbott, Darryl Adelaide / VanOsdol, Luke Andrew / Heald-Sargent, Taylor / Qiu, Longhui / Chen, Qing / Iovane, Andre / Zhang, Zheng / Abecassis, Michael M

    The Journal of general virology

    2019  Volume 100, Issue 12, Page(s) 1680–1694

    Abstract: CD34+ myeloid lineage progenitor cells are an important reservoir of latent human cytomegalovirus (HCMV), and differentiation to macrophages or dendritic cells (DCs) is known to cause reactivation of latent virus. Due to its species-specificity, murine ... ...

    Abstract CD34+ myeloid lineage progenitor cells are an important reservoir of latent human cytomegalovirus (HCMV), and differentiation to macrophages or dendritic cells (DCs) is known to cause reactivation of latent virus. Due to its species-specificity, murine models have been used to study mouse CMV (MCMV) latency and reactivation
    MeSH term(s) Animals ; Biomarkers ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/metabolism ; Bone Marrow Cells/virology ; Cell Differentiation/drug effects ; Cells, Cultured ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/virology ; Disease Models, Animal ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/virology ; Host-Pathogen Interactions ; Interleukin-4/pharmacology ; Kinetics ; Mice ; Myeloid Cells/drug effects ; Myeloid Cells/metabolism ; Myeloid Cells/virology ; Viral Tropism ; Virus Activation ; Virus Latency ; Virus Replication
    Chemical Substances Biomarkers ; Interleukin-4 (207137-56-2) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
    Language English
    Publishing date 2019-10-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001327
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  7. Article ; Online: A Rhesus Macaque Model of Pulmonary Nontuberculous Mycobacterial Disease.

    Winthrop, Kevin / Rivera, Andrea / Engelmann, Flora / Rose, Sasha / Lewis, Anne / Ku, Jennifer / Bermudez, Luiz / Messaoudi, Ilhem

    American journal of respiratory cell and molecular biology

    2016  Volume 54, Issue 2, Page(s) 170–176

    Abstract: In this study, we sought to develop a nonhuman primate model of pulmonary Mycobacterium avium complex (MAC) disease. Blood and bronchoalveolar lavage fluid were collected from three female rhesus macaques infected intrabronchially with escalating doses ... ...

    Abstract In this study, we sought to develop a nonhuman primate model of pulmonary Mycobacterium avium complex (MAC) disease. Blood and bronchoalveolar lavage fluid were collected from three female rhesus macaques infected intrabronchially with escalating doses of M. avium subsp. hominissuis. Immunity was determined by measuring cytokine levels, lymphocyte proliferation, and antigen-specific responses. Disease progression was monitored clinically and microbiologically with serial thoracic radiographs, computed tomography scans, and quantitative mycobacterial cultures. The animal subjected to the highest inoculum showed evidence of chronic pulmonary MAC disease. Therefore, rhesus macaques could provide a robust model in which to investigate host-pathogen interactions during MAC infection.
    MeSH term(s) Animals ; Antibodies, Bacterial/blood ; Bacterial Load ; Biopsy ; Bronchoalveolar Lavage Fluid/microbiology ; Cell Proliferation ; Chronic Disease ; Cytokines/blood ; Disease Models, Animal ; Female ; Immunoglobulin G/blood ; Lung/microbiology ; Lung/pathology ; Lymphocyte Activation ; Macaca mulatta ; Mycobacterium avium Complex/immunology ; Mycobacterium avium Complex/pathogenicity ; Mycobacterium avium-intracellulare Infection/blood ; Mycobacterium avium-intracellulare Infection/immunology ; Mycobacterium avium-intracellulare Infection/microbiology ; Mycobacterium avium-intracellulare Infection/pathology ; Respiratory Tract Infections/blood ; Respiratory Tract Infections/immunology ; Respiratory Tract Infections/microbiology ; Respiratory Tract Infections/pathology ; T-Lymphocytes/immunology ; T-Lymphocytes/microbiology ; Time Factors ; Tomography, X-Ray Computed
    Chemical Substances Antibodies, Bacterial ; Cytokines ; Immunoglobulin G
    Language English
    Publishing date 2016-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2015-0256RC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Autophagic Killing Effects against Mycobacterium tuberculosis by Alveolar Macrophages from Young and Aged Rhesus Macaques.

    Pacheco, Sophia A / Powers, Katelyn M / Engelmann, Flora / Messaoudi, Ilhem / Purdy, Georgiana E

    PloS one

    2013  Volume 8, Issue 6, Page(s) e66985

    Abstract: Non-human primates, notably rhesus macaques (Macaca mulatta, RM), provide a robust experimental model to investigate the immune response to and effective control of Mycobacterium tuberculosis infections. Changes in the function of immune cells and ... ...

    Abstract Non-human primates, notably rhesus macaques (Macaca mulatta, RM), provide a robust experimental model to investigate the immune response to and effective control of Mycobacterium tuberculosis infections. Changes in the function of immune cells and immunosenescence may contribute to the increased susceptibility of the elderly to tuberculosis. The goal of this study was to examine the impact of age on M. tuberculosis host-pathogen interactions following infection of primary alveolar macrophages derived from young and aged rhesus macaques. Of specific interest to us was whether the mycobactericidal capacity of autophagic macrophages was reduced in older animals since decreased autophagosome formation and autophagolysosomal fusion has been observed in other cells types of aged animals. Our data demonstrate that alveolar macrophages from old RM are as competent as those from young animals for autophagic clearance of M. tuberculosis infection and controlling mycobacterial replication. While our data do not reveal significant differences between alveolar macrophage responses to M. tuberculosis by young and old animals, these studies are the first to functionally characterize autophagic clearance of M. tuberculosis by alveolar macrophages from RM.
    MeSH term(s) Age Factors ; Animals ; Autophagy ; Macaca mulatta ; Macrophages, Alveolar/immunology ; Macrophages, Alveolar/microbiology ; Mycobacterium tuberculosis/immunology
    Language English
    Publishing date 2013-06-18
    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.0066985
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  9. Article ; Online: Bacterial artificial chromosome derived simian varicella virus is pathogenic in vivo.

    Meyer, Christine / Dewane, Jesse / Haberthur, Kristen / Engelmann, Flora / Arnold, Nicole / Gray, Wayne / Messaoudi, Ilhem

    Virology journal

    2013  Volume 10, Page(s) 278

    Abstract: Background: Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that infects humans and results in chickenpox and herpes zoster. A number of VZV genes remain functionally uncharacterized and since VZV is an obligate human pathogen, rigorous ... ...

    Abstract Background: Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that infects humans and results in chickenpox and herpes zoster. A number of VZV genes remain functionally uncharacterized and since VZV is an obligate human pathogen, rigorous evaluation of VZV mutants in vivo remains challenging. Simian varicella virus (SVV) is homologous to VZV and SVV infection of rhesus macaques (RM) closely mimics VZV infection of humans. Recently the SVV genome was cloned as a bacterial artificial chromosome (BAC) and BAC-derived SVV displayed similar replication kinetics as wild-type (WT) SVV in vitro.
    Methods: RMs were infected with BAC-derived SVV or WT SVV at 4x10(5) PFU intrabronchially (N=8, 4 per group, sex and age matched). We collected whole blood (PBMC) and bronchoalveolar lavage (BAL) at various days post-infection (dpi) and sensory ganglia during latent infection (>84 dpi) at necropsy and compared disease progression, viral replication, immune response and the establishment of latency.
    Results: Viral replication kinetics and magnitude in bronchoalveolar lavage cells and whole blood as well as rash severity and duration were similar in RMs infected with SVV BAC or WT SVV. Moreover, SVV-specific B and T cell responses were comparable between BAC and WT-infected animals. Lastly, we measured viral DNA in sensory ganglia from both cohorts of infected RMs during latent infection.
    Conclusions: SVV BAC is as pathogenic and immunogenic as WT SVV in vivo. Thus, the SVV BAC genetic system combined with the rhesus macaque animal model can further our understanding of viral ORFs important for VZV pathogenesis and the development of second-generation vaccines.
    MeSH term(s) Animals ; Blood/virology ; Bronchoalveolar Lavage Fluid/virology ; Chickenpox/pathology ; Chickenpox/virology ; Chromosomes, Artificial, Bacterial ; Disease Models, Animal ; Ganglia, Sensory/virology ; Macaca mulatta ; Varicellovirus/genetics ; Varicellovirus/pathogenicity ; Virus Latency
    Keywords covid19
    Language English
    Publishing date 2013-09-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1743-422X
    ISSN (online) 1743-422X
    DOI 10.1186/1743-422X-10-278
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  10. Article ; Online: Abortive intrabronchial infection of rhesus macaques with varicella-zoster virus provides partial protection against simian varicella virus challenge.

    Meyer, Christine / Engelmann, Flora / Arnold, Nicole / Krah, David L / ter Meulen, Jan / Haberthur, Kristen / Dewane, Jesse / Messaoudi, Ilhem

    Journal of virology

    2015  Volume 89, Issue 3, Page(s) 1781–1793

    Abstract: Unlabelled: Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus and the etiological agent of varicella (chickenpox) and herpes zoster (HZ, shingles). Previously, inoculation of monkeys via the subcutaneous, intratracheal, intravenous, ... ...

    Abstract Unlabelled: Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus and the etiological agent of varicella (chickenpox) and herpes zoster (HZ, shingles). Previously, inoculation of monkeys via the subcutaneous, intratracheal, intravenous, or oral-nasal-conjunctival routes did not recapitulate all the hallmarks of VZV infection, including varicella, immunity, latency, and reactivation. Intrabronchial inoculation of rhesus macaques (RMs) with simian varicella virus (SVV), a homolog of VZV, recapitulates virologic and immunologic hallmarks of VZV infection in humans. Given that VZV is acquired primarily via the respiratory route, we investigated whether intrabronchial inoculation of RMs with VZV would result in a robust model. Despite the lack of varicella and viral replication in either the lungs or whole blood, all four RMs generated an immune response characterized by the generation of VZV-specific antibodies and T cells. Two of 4 VZV-inoculated RMs were challenged with SVV to determine cross-protection. VZV-immune RMs displayed no varicella rash and had lower SVV viral loads and earlier and stronger humoral and cellular immune responses than controls. In contrast to the results for SVV DNA, no VZV DNA was detected in sensory ganglia at necropsy. In summary, following an abortive VZV infection, RMs developed an adaptive immune response that conferred partial protection against SVV challenge. These data suggest that a replication-incompetent VZV vaccine that does not establish latency may provide sufficient protection against VZV disease and that VZV vaccination of RMs followed by SVV challenge provides a model to evaluate new vaccines and therapeutics against VZV.
    Importance: Although VZV vaccine strain Oka is attenuated, it can cause mild varicella, establish latency, and in rare cases, reactivate to cause herpes zoster (HZ). Moreover, studies suggest that the HZ vaccine (Zostavax) only confers short-lived immunity. The development of more efficacious vaccines would be facilitated by a robust animal model of VZV infection. The data presented in this report show that intrabronchial inoculation of rhesus macaques (RMs) with VZV resulted in an abortive VZV infection. Nevertheless, all animals generated a humoral and cellular immune response that conferred partial cross-protection against simian varicella virus (SVV) challenge. Additionally, VZV DNA was not detected in the sensory ganglia, suggesting that viremia might be required for the establishment of latency. Therefore, VZV vaccination of RMs followed by SVV challenge is a model that will support the development of vaccines that boost protective T cell responses against VZV.
    MeSH term(s) Animals ; Antibodies, Viral/blood ; Chickenpox/immunology ; Chickenpox/pathology ; Chickenpox/prevention & control ; Chickenpox/veterinary ; Cross Protection ; DNA, Viral/genetics ; DNA, Viral/isolation & purification ; Ganglia/virology ; Herpesvirus 3, Human/immunology ; Macaca mulatta ; Male ; Primate Diseases/immunology ; Primate Diseases/prevention & control ; T-Lymphocytes/immunology
    Chemical Substances Antibodies, Viral ; DNA, Viral
    Language English
    Publishing date 2015-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.03124-14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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