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Article ; Online: Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques.

Bollimpelli, Venkata S / Reddy, Pradeep B J / Gangadhara, Sailaja / Charles, Tysheena P / Burton, Samantha L / Tharp, Gregory K / Styles, Tiffany M / Labranche, Celia C / Smith, Justin C / Upadhyay, Amit A / Sahoo, Anusmita / Legere, Traci / Shiferaw, Ayalnesh / Velu, Vijayakumar / Yu, Tianwei / Tomai, Mark / Vasilakos, John / Kasturi, Sudhir P / Shaw, George M /

Montefiori, David / Bosinger, Steven E / Kozlowski, Pamela A / Pulendran, Bali / Derdeyn, Cynthia A / Hunter, Eric / Amara, Rama R

Nature communications

2023 Volume 14, Issue 1, Page(s) 4789

Abstract: Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 simian-human ...

Abstract	Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 simian-human immunodeficiency virus (SHIV) challenges in female macaques. Both routes of vaccination induce comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlates positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlates only with serum neutralizing activity. MVA-ID immunizations induce greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlates negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses.
MeSH term(s)	Animals ; Humans ; Female ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Vaccinia/prevention & control ; Macaca mulatta ; Simian Immunodeficiency Virus ; Vaccinia virus ; Vaccination ; HIV ; Antibodies, Viral
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-08-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40430-7
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Article ; Online: Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

Viox, Elise G / Hoang, Timothy N / Upadhyay, Amit A / Nchioua, Rayhane / Hirschenberger, Maximilian / Strongin, Zachary / Tharp, Gregory K / Pino, Maria / Nguyen, Kevin / Harper, Justin L / Gagne, Matthew / Marciano, Shir / Boddapati, Arun K / Pellegrini, Kathryn L / Pradhan, Arpan / Tisoncik-Go, Jennifer / Whitmore, Leanne S / Karunakaran, Kirti A / Roy, Melissa /

Science immunology

2023 Volume 8, Issue 85, Page(s) eadg0033

Abstract: Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in ... ...

Abstract	Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2-infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163
MeSH term(s)	Animals ; Interferon Type I/pharmacology ; SARS-CoV-2 ; Macaca mulatta ; COVID-19 ; Virus Replication ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Inflammation/drug therapy
Chemical Substances	Interferon Type I ; Antiviral Agents
Language	English
Publishing date	2023-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adg0033
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Article: Covalent conjugation of polyethyleneimine on biodegradable microparticles for delivery of plasmid DNA vaccines.

Kasturi, Sudhir P / Sachaphibulkij, Karishma / Roy, Krishnendu

Biomaterials

2005 Volume 26, Issue 32, Page(s) 6375–6385

Abstract: Microparticle-based delivery of nucleic acids has gained particular attention in recent years in view of improving the potency of DNA vaccination. Such improvement has been reported by encapsulation of pDNA within biodegradable microparticles or through ... ...

Abstract	Microparticle-based delivery of nucleic acids has gained particular attention in recent years in view of improving the potency of DNA vaccination. Such improvement has been reported by encapsulation of pDNA within biodegradable microparticles or through surface adsorption on cationic microparticles. However, the intrinsic intracellular barriers for gene delivery to antigen presenting cells (APCs) have not been adequately addressed in the rational design of delivery systems for DNA vaccines. Here we report synthesis and characterization of biodegradable microparticles that (a) can passively target phagocytic APCs, (b) have intrinsic buffering ability that might allow for enhanced phagosomal escape, (c) are not cytotoxic and (d) have improved APC transfection efficiency. Branched polyethyleneimine (b-PEI) was covalently conjugated using carbodiimide chemistry to the surface of poly(lactide-coglycolide) (PLGA) microparticles to create cationic microparticles capable of simultaneously delivering both DNA vaccines as well as other immunomodulatory agents (cytokines or nucleic acids) within a single injectable delivery vehicle. Our results indicate that covalent conjugation of b-PEI allows efficient surface loading of nucleic acids, introduces intrinsic buffering properties to PLGA particles and enhances transfection of phagocytic cells without affecting the cytocompatibility of PLGA carriers.
MeSH term(s)	Absorbable Implants ; Animals ; Cell Line ; Cells, Cultured ; Coated Materials, Biocompatible/chemistry ; Drug Carriers/chemistry ; Macrophages/metabolism ; Materials Testing/methods ; Mice ; Microspheres ; Particle Size ; Plasmids/administration & dosage ; Plasmids/chemistry ; Plasmids/pharmacokinetics ; Polyethyleneimine/chemistry ; Transfection/methods ; Vaccines, DNA/administration & dosage ; Vaccines, DNA/chemistry ; Vaccines, DNA/pharmacokinetics
Chemical Substances	Coated Materials, Biocompatible ; Drug Carriers ; Vaccines, DNA ; Polyethyleneimine (9002-98-6)
Language	English
Publishing date	2005-11
Publishing country	Netherlands
Document type	Evaluation Studies ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2005.03.043
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Article: Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques.

Hoang, Timothy N / Viox, Elise G / Upadhyay, Amit A / Strongin, Zachary / Tharp, Gregory K / Pino, Maria / Nchioua, Rayhane / Hirschenberger, Maximilian / Gagne, Matthew / Nguyen, Kevin / Harper, Justin L / Marciano, Shir / Boddapati, Arun K / Pellegrini, Kathryn L / Tisoncik-Go, Jennifer / Whitmore, Leanne S / Karunakaran, Kirti A / Roy, Melissa / Kirejczyk, Shannon /

Curran, Elizabeth H / Wallace, Chelsea / Wood, Jennifer S / Connor-Stroud, Fawn / Kasturi, Sudhir P / Levit, Rebecca D / Gale, Michael / Vanderford, Thomas H / Silvestri, Guido / Busman-Sahay, Kathleen / Estes, Jacob D / Vaccari, Monica / Douek, Daniel C / Sparrer, Konstantin M J / Kirchhoff, Frank / Johnson, R Paul / Schreiber, Gideon / Bosinger, Steven E / Paiardini, Mirko

bioRxiv : the preprint server for biology

2022

Abstract: Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated ...

Abstract	Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-β pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.10.21.512606
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Article ; Online: Vaccine-induced plasmablast responses in rhesus macaques: phenotypic characterization and a source for generating antigen-specific monoclonal antibodies.

Silveira, Eduardo L V / Kasturi, Sudhir P / Kovalenkov, Yevgeniy / Rasheed, Ata Ur / Yeiser, Patryce / Jinnah, Zarpheen S / Legere, Traci H / Pulendran, Bali / Villinger, Francois / Wrammert, Jens

Journal of immunological methods

2015 Volume 416, Page(s) 69–83

Abstract: Over 100 broadly neutralizing antibodies have been isolated from a minority of HIV infected patients, but the steps leading to the selection of plasma cells producing such antibodies remain incompletely understood, hampering the development of vaccines ... ...

Abstract	Over 100 broadly neutralizing antibodies have been isolated from a minority of HIV infected patients, but the steps leading to the selection of plasma cells producing such antibodies remain incompletely understood, hampering the development of vaccines able to elicit them. Rhesus macaques have become a preferred animal model system used to study SIV/HIV, for the characterization and development of novel therapeutics and vaccines as well as to understand pathogenesis. However, most of our knowledge about the dynamics of antibody responses is limited to the analysis of serum antibodies or monoclonal antibodies generated from memory B cells. In a vaccine setting, relatively little is known about the early cellular responses that elicit long-lived plasma cells and memory B cells and the tools to dissect plasmablast responses are not available in macaques. In the current study, we show that the majority (>80%) of the vaccine-induced plasmablast response are antigen-specific by functional ELISPOT assays. While plasmablasts are easily defined and isolated in humans, those same phenotypic markers have not been useful for identifying macaque plasmablasts. Here we describe an approach that allows for the isolation and single cell sorting of vaccine-induced plasmablasts. Finally, we show that isolated plasmablasts can be used to efficiently recover antigen-specific monoclonal antibodies through single cell expression cloning. This will allow detailed studies of the early plasmablast responses in rhesus macaques, enabling the characterization of both their repertoire breadth as well as the epitope specificity and functional qualities of the antibodies they produce, not only in the context of SIV/HIV vaccines but for many other pathogens/vaccines as well.
MeSH term(s)	AIDS Vaccines/immunology ; Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Antigens/immunology ; B-Lymphocytes/immunology ; Cell Separation/methods ; Enzyme-Linked Immunospot Assay/methods ; HIV/immunology ; HIV Infections/immunology ; Immunologic Memory/immunology ; Macaca mulatta/immunology ; Macaca mulatta/virology ; Models, Animal ; Plasma Cells/immunology ; SAIDS Vaccines/immunology ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/immunology ; Vaccines/immunology
Chemical Substances	AIDS Vaccines ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antigens ; SAIDS Vaccines ; Vaccines
Language	English
Publishing date	2015-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2014.11.003
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Article ; Online: The stimulation of CD8+ T cells by dendritic cells pulsed with polyketal microparticles containing ion-paired protein antigen and poly(inosinic acid)-poly(cytidylic acid).

Heffernan, Michael J / Kasturi, Sudhir P / Yang, Stephen C / Pulendran, Bali / Murthy, Niren

Biomaterials

2008 Volume 30, Issue 5, Page(s) 910–918

Abstract: New adjuvants and delivery strategies are needed to optimize the ability of protein-based vaccines to elicit CD8(+) T cell responses. We have developed a model vaccine formulation containing ovalbumin (OVA) and the double-stranded RNA analog poly( ... ...

Abstract	New adjuvants and delivery strategies are needed to optimize the ability of protein-based vaccines to elicit CD8(+) T cell responses. We have developed a model vaccine formulation containing ovalbumin (OVA) and the double-stranded RNA analog poly(inosinic acid)-poly(cytidylic acid) (poly(I:C)), a TLR3 agonist. OVA and poly(I:C) were each ion-paired to cetyltrimethylammonium bromide (CTAB) to produce hydrophobic complexes, which were co-encapsulated in pH-sensitive polyketal (PK3) microparticles (1-3 microm) using a single emulsion method. Loading levels ranged from 13.6 to 18.8 microg/mg OVA and 4.8 to 10.3 microg/mg poly(I:C). Murine splenic dendritic cells (DCs) pulsed with PK3-OVA-poly(I:C) microparticles, at antigen doses of 0.01 and 0.1 microg/mL, induced a higher percentage of IFNgamma-producing CD8(+) T cells than DCs treated with PK3-OVA particles or soluble OVA/poly(I:C). A higher antigen dose (1 microg/mL) was less effective, which can be attributed to CTAB toxicity. At the lowest antigen dose (0.01 microg/mL), PK3-OVA-poly(I:C) microparticles also enhanced TNF-alpha and IL-2 production in CD8(+) T cells. These data demonstrate the potential of polyketal microparticles in formulating effective CD8(+) T cell-inducing vaccines comprising protein antigens and dsRNA adjuvants.
MeSH term(s)	Animals ; Antigens/chemistry ; Antigens/immunology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Dendritic Cells/chemistry ; Dendritic Cells/immunology ; Mice ; Microspheres ; Poly I-C/chemistry ; Poly I-C/immunology
Chemical Substances	Antigens ; Poly I-C (O84C90HH2L)
Language	English
Publishing date	2008-11-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2008.10.034
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Article ; Online: Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques.

Iyer, Smita S / Gangadhara, Sailaja / Victor, Blandine / Shen, Xiaoying / Chen, Xuemin / Nabi, Rafiq / Kasturi, Sudhir P / Sabula, Michael J / Labranche, Celia C / Reddy, Pradeep B J / Tomaras, Georgia D / Montefiori, David C / Moss, Bernard / Spearman, Paul / Pulendran, Bali / Kozlowski, Pamela A / Amara, Rama Rao

Journal of virology

2016 Volume 90, Issue 19, Page(s) 8842–8854

Abstract: Unlabelled: The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective ... ...

Abstract	Unlabelled: The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations with DNA (D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the second MVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of seven DNA/MVA and VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control. Importance: The development of an effective HIV vaccine remains a global necessity for preventing HIV infection and reducing the burden of AIDS. While this goal represents a formidable challenge, the modest efficacy of the RV144 trial indicates that multicomponent vaccination regimens that elicit both cellular and humoral immune responses can prevent HIV infection in humans. However, whether protein immunizations synergize with DNA prime-viral vector boosts to enhance cellular and humoral immune responses remains poorly understood. We addressed this question in a nonhuman primate model, and our findings show benefit for sequential protein immunization combined with a potent adjuvant in boosting antibody titers induced by a preceding DNA/MVA immunization. This promising strategy can be further developed to enhance neutralizing antibody responses and boost CD8 T cells to provide robust protection and viral control.
MeSH term(s)	Animals ; Antibodies, Viral/blood ; Antibody Formation ; Drug Carriers ; Macaca mulatta ; SAIDS Vaccines/administration & dosage ; SAIDS Vaccines/genetics ; SAIDS Vaccines/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/immunology ; Treatment Outcome ; Vaccines, DNA/administration & dosage ; Vaccines, DNA/genetics ; Vaccines, DNA/immunology ; Vaccines, Synthetic/administration & dosage ; Vaccines, Synthetic/genetics ; Vaccines, Synthetic/immunology ; Vaccines, Virus-Like Particle/administration & dosage ; Vaccines, Virus-Like Particle/genetics ; Vaccines, Virus-Like Particle/immunology ; Vaccinia virus/genetics ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/immunology ; Viremia/prevention & control
Chemical Substances	Antibodies, Viral ; Drug Carriers ; SAIDS Vaccines ; Vaccines, DNA ; Vaccines, Synthetic ; Vaccines, Virus-Like Particle ; Viral Envelope Proteins
Language	English
Publishing date	2016-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01163-16
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Article ; Online: Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques

Hoang, Timothy N. / Viox, Elise G. / Upadhyay, Amit A. / Strongin, Zachary / Tharp, Gregory K. / Pino, Maria / Nchioua, Rayhane / Hirschenberger, Maximilian / Gagne, Matthew / Nguyen, Kevin / Harper, Justin L. / Marciano, Shir / Boddapati, Arun K. / Pellegrini, Kathryn L. / Tisoncik-Go, Jennifer / Whitmore, Leanne S. / Karunakaran, Kirti A. / Roy, Melissa / Kirejczyk, Shannon /

Curran, Elizabeth H. / Wallace, Chelsea / Wood, Jennifer S. / Connor-Stroud, Fawn / Kasturi, Sudhir P. / Levit, Rebecca D. / Gale, Michael / Vanderford, Thomas H. / Silvestri, Guido / Busman-Sahay, Kathleen / Estes, Jacob D. / Vaccari, Monica / Douek, Daniel C. / Sparrer, Konstantin M.J. / Kirchhoff, Frank / Johnson, R. Paul / Schreiber, Gideon / Bosinger, Steven E. / Paiardini, Mirko

bioRxiv

Abstract	Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1- inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-β pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.
Keywords	covid19
Language	English
Publishing date	2022-10-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.10.21.512606
Database	COVID19

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Article: Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

Hoang, Timothy N / Pino, Maria / Boddapati, Arun K / Viox, Elise G / Starke, Carly E / Upadhyay, Amit A / Gumber, Sanjeev / Busman-Sahay, Kathleen / Strongin, Zachary / Harper, Justin L / Tharp, Gregory K / Pellegrini, Kathryn L / Kirejczyk, Shannon / Zandi, Keivan / Tao, Sijia / Horton, Tristan R / Beagle, Elizabeth N / Mahar, Ernestine A / Lee, Michelle Yh /

Cohen, Joyce / Jean, Sherrie M / Wood, Jennifer S / Connor-Stroud, Fawn / Stammen, Rachelle L / Delmas, Olivia M / Wang, Shelly / Cooney, Kimberly A / Sayegh, Michael N / Wang, Lanfang / Weiskopf, Daniela / Filev, Peter D / Waggoner, Jesse / Piantadosi, Anne / Kasturi, Sudhir P / Al-Shakhshir, Hilmi / Ribeiro, Susan P / Sekaly, Rafick P / Levit, Rebecca D / Estes, Jacob D / Vanderford, Thomas H / Schinazi, Raymond F / Bosinger, Steven E / Paiardini, Mirko

bioRxiv : the preprint server for biology

2020

Abstract: Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti- ... ...

Abstract	Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.09.16.300277
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Article ; Online: Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques.

Hoang, Timothy N / Pino, Maria / Boddapati, Arun K / Viox, Elise G / Starke, Carly E / Upadhyay, Amit A / Gumber, Sanjeev / Nekorchuk, Michael / Busman-Sahay, Kathleen / Strongin, Zachary / Harper, Justin L / Tharp, Gregory K / Pellegrini, Kathryn L / Kirejczyk, Shannon / Zandi, Keivan / Tao, Sijia / Horton, Tristan R / Beagle, Elizabeth N / Mahar, Ernestine A /

Lee, Michelle Y H / Cohen, Joyce / Jean, Sherrie M / Wood, Jennifer S / Connor-Stroud, Fawn / Stammen, Rachelle L / Delmas, Olivia M / Wang, Shelly / Cooney, Kimberly A / Sayegh, Michael N / Wang, Lanfang / Filev, Peter D / Weiskopf, Daniela / Silvestri, Guido / Waggoner, Jesse / Piantadosi, Anne / Kasturi, Sudhir P / Al-Shakhshir, Hilmi / Ribeiro, Susan P / Sekaly, Rafick P / Levit, Rebecca D / Estes, Jacob D / Vanderford, Thomas H / Schinazi, Raymond F / Bosinger, Steven E / Paiardini, Mirko

Cell

2020 Volume 184, Issue 2, Page(s) 460–475.e21

Abstract: SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the ... ...

Abstract	SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/administration & dosage ; Azetidines/administration & dosage ; COVID-19/drug therapy ; COVID-19/immunology ; COVID-19/physiopathology ; Cell Death/drug effects ; Cell Degranulation/drug effects ; Disease Models, Animal ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/immunology ; Janus Kinases/antagonists & inhibitors ; Lung/drug effects ; Lung/immunology ; Lung/pathology ; Lymphocyte Activation/drug effects ; Macaca mulatta ; Macrophages, Alveolar/immunology ; Neutrophil Infiltration/drug effects ; Purines/administration & dosage ; Pyrazoles/administration & dosage ; SARS-CoV-2/physiology ; Severity of Illness Index ; Sulfonamides/administration & dosage ; T-Lymphocytes/immunology ; Virus Replication/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Azetidines ; Purines ; Pyrazoles ; Sulfonamides ; Janus Kinases (EC 2.7.10.2) ; baricitinib (ISP4442I3Y)
Language	English
Publishing date	2020-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.11.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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