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Article ; Online: Embracing the heterogeneity of natural viruses in mouse studies.

Fiege, Jessica K / Langlois, Ryan A

2022 Volume 103, Issue 6

Abstract: Animal models are a critical tool in modern biology. To increase reproducibility and to reduce confounding variables modern animal models exclude many microbes, including key natural commensals and pathogens. Here we discuss recent strategies to ... ...

Abstract	Animal models are a critical tool in modern biology. To increase reproducibility and to reduce confounding variables modern animal models exclude many microbes, including key natural commensals and pathogens. Here we discuss recent strategies to incorporate a natural microbiota to laboratory mouse models and the impacts the microbiota has on immune responses, with a focus on viruses.
MeSH term(s)	Animals ; Disease Models, Animal ; Mice ; Microbiota ; Reproducibility of Results ; Symbiosis ; Viruses/genetics
Language	English
Publishing date	2022-06-23
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.0.001758
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Article ; Online: Comparison of mouse models of microbial experience reveals differences in microbial diversity and response to vaccination.

Sanders, Autumn E / Arnesen, Henriette / Shepherd, Frances K / Putri, Dira S / Fiege, Jessica K / Pierson, Mark J / Roach, Shanley N / Carlsen, Harald / Masopust, David / Boysen, Preben / Langlois, Ryan A

mSphere

2024 Volume 9, Issue 2, Page(s) e0065423

Abstract: Specific pathogen-free (SPF) laboratory mice dominate preclinical studies for immunology and vaccinology. Unfortunately, SPF mice often fail to accurately model human responses to vaccination and other immunological perturbations. Several groups have ... ...

Abstract	Specific pathogen-free (SPF) laboratory mice dominate preclinical studies for immunology and vaccinology. Unfortunately, SPF mice often fail to accurately model human responses to vaccination and other immunological perturbations. Several groups have taken different approaches to introduce additional microbial experience to SPF mice to better model human immune experience. How these different models compare is unknown. Here, we directly compare three models: housing SPF mice in a microbe-rich barn-like environment (feralizing), adding wild-caught mice to the barn-like environment (fer-cohoused), or cohousing SPF mice with pet store mice in a barrier facility (pet-cohoused); the two latter representing different murine sources of microbial transmission. Pet-cohousing mice resulted in the greatest microbial exposure. Feralizing alone did not result in the transmission of any pathogens tested, while fer-cohousing resulted in the transmission of several picornaviruses. Murine astrovirus 2, the most common pathogen from pet store mice, was absent from the other two model systems. Previously, we had shown that pet-cohousing reduced the antibody response to vaccination compared with SPF mice. This was not recapitulated in either the feralized or fer-cohoused mice. These data indicate that not all dirty mouse models are equivalent in either microbial experience or immune responses to vaccination. These disparities suggest that more cross model comparisons are needed but also represent opportunities to uncover microbe combination-specific phenotypes and develop more refined experimental models. Given the breadth of microbes encountered by humans across the globe, multiple model systems may be needed to accurately recapitulate heterogenous human immune responses.IMPORTANCEAnimal models are an essential tool for evaluating clinical interventions. Unfortunately, they can often fail to accurately predict outcomes when translated into humans. This failure is due in part to a lack of natural infections experienced by most laboratory animals. To improve the mouse model, we and others have exposed laboratory mice to microbes they would experience in the wild. Although these models have been growing in popularity, these different models have not been specifically compared. Here, we directly compare how three different models of microbial experience impact the immune response to influenza vaccination. We find that these models are not the same and that the degree of microbial exposure affects the magnitude of the response to vaccination. These results provide an opportunity for the field to continue comparing and contrasting these systems to determine which models best recapitulate different aspects of the human condition.
MeSH term(s)	Animals ; Mice ; Humans ; Disease Models, Animal ; Immunity ; Specific Pathogen-Free Organisms ; Vaccination
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Journal Article
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/msphere.00654-23
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Article ; Online: Investigating influenza A virus infection: tools to track infection and limit tropism.

Fiege, Jessica K / Langlois, Ryan A

Journal of virology

2015 Volume 89, Issue 12, Page(s) 6167–6170

Abstract: Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity, pathogenesis, and transmission will be critical for the development of therapeutic ... ...

Abstract	Influenza A viruses display a broad cellular tropism within the respiratory tracts of mammalian hosts. Uncovering the relationship between tropism and virus immunity, pathogenesis, and transmission will be critical for the development of therapeutic interventions. Here we discuss recent developments of several recombinant strains of influenza A virus. These viruses have inserted reporters to track tropism, microRNA target sites to restrict tropism, or barcodes to assess transmission dynamics, expanding our understanding of pathogen-host interactions.
MeSH term(s)	Animals ; Genes, Reporter ; Host-Pathogen Interactions ; Humans ; Influenza A virus/genetics ; Influenza A virus/physiology ; Molecular Biology/methods ; Viral Tropism ; Virology/methods
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00462-15
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Article ; Online: Respiratory Influenza Virus Infection Causes Dynamic Tuft Cell and Innate Lymphoid Cell Changes in the Small Intestine.

Roach, Shanley N / Fiege, Jessica K / Shepherd, Frances K / Wiggen, Talia D / Hunter, Ryan C / Langlois, Ryan A

Journal of virology

2022 Volume 96, Issue 9, Page(s) e0035222

Abstract: Influenza A viruses (IAV) can cause severe disease and death in humans. IAV infection and the accompanying immune response can result in systemic inflammation, leading to intestinal damage and disruption of the intestinal microbiome. Here, we demonstrate ...

Abstract	Influenza A viruses (IAV) can cause severe disease and death in humans. IAV infection and the accompanying immune response can result in systemic inflammation, leading to intestinal damage and disruption of the intestinal microbiome. Here, we demonstrate that a specific subset of epithelial cells, tuft cells, increase across the small intestine during active respiratory IAV infection. Upon viral clearance, tuft cell numbers return to baseline levels. Intestinal tuft cell increases were not protective against disease, as animals with either increased tuft cells or a lack of tuft cells did not have any change in disease morbidity after infection. Respiratory IAV infection also caused transient increases in type 1 and 2 innate lymphoid cells (ILC1 and ILC2, respectively) in the small intestine. ILC2 increases were significantly blunted in the absence of tuft cells, whereas ILC1s were unaffected. Unlike the intestines, ILCs in the lungs were not altered in the absence of tuft cells. This work establishes that respiratory IAV infection causes dynamic changes to tuft cells and ILCs in the small intestines and that tuft cells are necessary for the infection-induced increase in small intestine ILC2s. These intestinal changes in tuft cell and ILC populations may represent unexplored mechanisms preventing systemic infection and/or contributing to severe disease in humans with preexisting conditions.
MeSH term(s)	Animals ; Enteritis/immunology ; Enteritis/physiopathology ; Enteritis/virology ; Humans ; Immunity, Innate ; Influenza A virus/immunology ; Intestine, Small/cytology ; Intestine, Small/virology ; Lymphocytes/immunology ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/physiopathology ; Orthomyxoviridae Infections/virology
Language	English
Publishing date	2022-04-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00352-22
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Article ; Online: Genetic ancestry effects on the response to viral infection are pervasive but cell type specific.

Randolph, Haley E / Fiege, Jessica K / Thielen, Beth K / Mickelson, Clayton K / Shiratori, Mari / Barroso-Batista, João / Langlois, Ryan A / Barreiro, Luis B

Science (New York, N.Y.)

2021 Volume 374, Issue 6571, Page(s) 1127–1133

Abstract: Humans differ in their susceptibility to infectious disease, partly owing to variation in the immune response after infection. We used single-cell RNA sequencing to quantify variation in the response to influenza infection in peripheral blood mononuclear ...

Abstract	Humans differ in their susceptibility to infectious disease, partly owing to variation in the immune response after infection. We used single-cell RNA sequencing to quantify variation in the response to influenza infection in peripheral blood mononuclear cells from European- and African-ancestry males. Genetic ancestry effects are common but highly cell type specific. Higher levels of European ancestry are associated with increased type I interferon pathway activity in early infection, which predicts reduced viral titers at later time points. Substantial population-associated variation is explained by cis
MeSH term(s)	Adult ; Black or African American/genetics ; Aged ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/physiopathology ; Disease Susceptibility ; Gene Expression Regulation ; Genetic Variation ; Humans ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza, Human/genetics ; Influenza, Human/immunology ; Interferon Type I/immunology ; Interferon Type I/metabolism ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/virology ; Male ; Middle Aged ; Quantitative Trait Loci ; Severity of Illness Index ; Single-Cell Analysis ; Transcription, Genetic ; Viral Load ; White People/genetics ; Young Adult
Chemical Substances	Interferon Type I
Language	English
Publishing date	2021-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abg0928
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Article ; Online: Negative Regulation of Memory Phenotype CD8 T Cell Conversion by Adhesion and Degranulation-Promoting Adapter Protein.

Fiege, Jessica K / Burbach, Brandon J / Shimizu, Yoji

Journal of immunology (Baltimore, Md. : 1950)

2015 Volume 195, Issue 7, Page(s) 3119–3128

Abstract: The maintenance of T cell repertoire diversity involves the entry of newly developed T cells, as well as the maintenance of memory T cells generated from previous infections. This balance depends on competition for a limited amount of homeostatic ... ...

Abstract	The maintenance of T cell repertoire diversity involves the entry of newly developed T cells, as well as the maintenance of memory T cells generated from previous infections. This balance depends on competition for a limited amount of homeostatic cytokines and interaction with self-peptide MHC class I. In the absence of prior infection, memory-like or memory phenotype (MP) CD8 T cells can arise from homeostatic cytokine exposure during neonatal lymphopenia. Aside from downstream cytokine signaling, little is known about the regulation of the conversion of naive CD8 T cells to MP CD8 T cells during acute lymphopenia. We have identified a novel negative regulatory role for adhesion and degranulation-promoting adapter protein (ADAP) in CD8 T cell function. We show that in the absence of ADAP, naive CD8 T cells exhibit a diminished response to stimulatory Ag, but an enhanced response to weak agonist-altered peptide ligands. ADAP-deficient mice exhibit more MP CD8 T cells that occur following thymic emigration and are largely T cell intrinsic. Naive ADAP-deficient CD8 T cells are hyperresponsive to lymphopenia in vivo and exhibit enhanced activation of STAT5 and homeostatic Ag-independent proliferation in response to IL-15. Our results indicate that ADAP dampens naive CD8 T cell responses to lymphopenia and IL-15, and they demonstrate a novel Ag-independent function for ADAP in the suppression of MP CD8 T cell generation.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/immunology ; Animals ; Antigen-Antibody Reactions/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Enzyme Activation/immunology ; Immunologic Memory/immunology ; Interleukin-15/immunology ; Lymphopenia/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; STAT5 Transcription Factor/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Fyb protein, mouse ; Interleukin-15 ; STAT5 Transcription Factor
Language	English
Publishing date	2015-10-01
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.1402670
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Article ; Online: Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection.

Fiege, Jessica K / Beura, Lalit K / Burbach, Brandon J / Shimizu, Yoji

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 197, Issue 6, Page(s) 2079–2089

Abstract: During acute infections, naive Ag-specific CD8 T cells are activated and differentiate into effector T cells, most of which undergo contraction after pathogen clearance. A small population of CD8 T cells persists as memory to protect against future ... ...

Abstract	During acute infections, naive Ag-specific CD8 T cells are activated and differentiate into effector T cells, most of which undergo contraction after pathogen clearance. A small population of CD8 T cells persists as memory to protect against future infections. We investigated the role of adhesion- and degranulation-promoting adapter protein (ADAP) in promoting CD8 T cell responses to a systemic infection. Naive Ag-specific CD8 T cells lacking ADAP exhibited a modest expansion defect early after Listeria monocytogenes or vesicular stomatitis virus infection but comparable cytolytic function at the peak of response. However, reduced numbers of ADAP-deficient CD8 T cells were present in the spleen after the peak of the response. ADAP deficiency resulted in a greater frequency of CD127(+) CD8 memory precursors in secondary lymphoid organs during the contraction phase. Reduced numbers of ADAP-deficient killer cell lectin-like receptor G1(-) CD8 resident memory T (TRM) cell precursors were present in a variety of nonlymphoid tissues at the peak of the immune response, and consequently the total numbers of ADAP-deficient TRM cells were reduced at memory time points. TRM cells that did form in the absence of ADAP were defective in effector molecule expression. ADAP-deficient TRM cells exhibited impaired effector function after Ag rechallenge, correlating with defects in their ability to form T cell-APC conjugates. However, ADAP-deficient TRM cells responded to TGF-β signals and recruited circulating memory CD8 T cells. Thus, ADAP regulates CD8 T cell differentiation events following acute pathogen challenge that are critical for the formation and selected functions of TRM cells in nonlymphoid tissues.
MeSH term(s)	Acute Disease ; Adaptor Proteins, Signal Transducing/physiology ; Animals ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/physiology ; Cell Differentiation ; Cytokines/biosynthesis ; Immunologic Memory ; Infections/immunology ; Listeriosis/immunology ; Mice ; Mice, Inbred C57BL ; Vesicular Stomatitis/immunology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cytokines ; Fyb protein, mouse
Language	English
Publishing date	2016-08-12
Publishing country	United States
Document type	Journal Article
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.1501805
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Article ; Online: Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function.

Dumm, Rebekah E / Fiege, Jessica K / Waring, Barbara M / Kuo, Chay T / Langlois, Ryan A / Heaton, Nicholas S

Nature communications

2019 Volume 10, Issue 1, Page(s) 779

Abstract: Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell ... ...

Abstract	Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell death; some cells can intrinsically clear the virus and persist in the host long-term. To determine if any cells can survive direct IBV infection, we here generate a recombinant IBV capable of activating a host-cell reporter to permanently label all infected cells. Using this system, we demonstrate that IBV infection leads to the formation of a survivor cell population in the proximal airways that are ciliated-like, but transcriptionally and phenotypically distinct from both actively infected and bystander ciliated cells. We also show that survivor cells are critical to maintain respiratory barrier function. These results highlight a host response pathway that preserves the epithelium to limit the severity of IBV disease.
MeSH term(s)	A549 Cells ; Animals ; Chick Embryo ; Chickens ; Epithelial Cells/virology ; Female ; Humans ; Influenza B virus/pathogenicity ; Male ; Mice, Inbred C57BL
Language	English
Publishing date	2019-02-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-08617-z
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Article ; Online: Distinct antiviral signatures revealed by the magnitude and round of influenza virus replication in vivo.

Sjaastad, Louisa E / Fay, Elizabeth J / Fiege, Jessica K / Macchietto, Marissa G / Stone, Ian A / Markman, Matthew W / Shen, Steven / Langlois, Ryan A

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

2018 Volume 115, Issue 38, Page(s) 9610–9615

Abstract: Influenza virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used a series of single-cycle ...

Abstract	Influenza virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used a series of single-cycle reporter viruses. These viral probes demonstrated cells in vivo harbor a range in magnitude of virus replication. Transcriptional profiling of cells supporting different levels of replication revealed tiers of IFN-stimulated gene expression. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective antiviral signature, while cells with high replication expressed a unique reserve set of antiviral genes. Finally, we used these single-cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection of epithelial cell subsets mediated by IFN in vivo. Together these results highlight the complexity of virus-host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.
MeSH term(s)	Animals ; Dogs ; Epithelial Cells/immunology ; Epithelial Cells/virology ; Gene Expression Profiling/methods ; HEK293 Cells ; High-Throughput Nucleotide Sequencing ; Host-Pathogen Interactions/immunology ; Humans ; Influenza A virus/isolation & purification ; Influenza A virus/physiology ; Influenza, Human/immunology ; Influenza, Human/pathology ; Influenza, Human/virology ; Interferons/immunology ; Lung/cytology ; Lung/immunology ; Lung/pathology ; Lung/virology ; Madin Darby Canine Kidney Cells ; Mice, Inbred C57BL ; RNA, Viral/isolation & purification ; Sequence Analysis, DNA ; Virus Replication/immunology
Chemical Substances	RNA, Viral ; Interferons (9008-11-1)
Language	English
Publishing date	2018-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1807516115
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Article ; Online: MicroRNA-Based Attenuation of Influenza Virus across Susceptible Hosts.

Waring, Barbara M / Sjaastad, Louisa E / Fiege, Jessica K / Fay, Elizabeth J / Reyes, Ismarc / Moriarity, Branden / Langlois, Ryan A

Journal of virology

2018 Volume 92, Issue 2

Abstract: Influenza A virus drives significant morbidity and mortality in humans and livestock. Annual circulation of the virus in livestock and waterfowl contributes to severe economic disruption and increases the risk of zoonotic transmission of novel strains ... ...

Abstract	Influenza A virus drives significant morbidity and mortality in humans and livestock. Annual circulation of the virus in livestock and waterfowl contributes to severe economic disruption and increases the risk of zoonotic transmission of novel strains into the human population, where there is no preexisting immunity. Seasonal vaccinations in humans help prevent infection and can reduce symptoms when infection does occur. However, current vaccination regimens available for livestock are limited in part due to safety concerns regarding reassortment/recombination with circulating strains. Therefore, inactivated vaccines are used instead of the more immunostimulatory live attenuated vaccines. MicroRNAs (miRNAs) have been used previously to generate attenuated influenza A viruses for use as a vaccine. Here, we systematically targeted individual influenza gene mRNAs using the same miRNA to determine the segment(s) that yields maximal attenuation potential. This analysis demonstrated that targeting of NP mRNA most efficiently ablates replication. We further increased the plasticity of miRNA-mediated attenuation of influenza A virus by exploiting a miRNA, miR-21, that is ubiquitously expressed across influenza-susceptible hosts. In order to construct this targeted virus, we used CRISPR/Cas9 to eliminate the universally expressed miR-21 from MDCK cells. miR-21-targeted viruses were attenuated in human, mouse, canine, and avian cells and drove protective immunity in mice. This strategy has the potential to enhance the safety of live attenuated vaccines in humans and zoonotic reservoirs.
MeSH term(s)	Animals ; Cross Reactions/immunology ; Disease Models, Animal ; Dogs ; Gene Knockout Techniques ; Gene Silencing ; Genes, Viral ; HEK293 Cells ; Host-Pathogen Interactions/immunology ; Humans ; Influenza A Virus, H1N1 Subtype/genetics ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A virus/genetics ; Influenza A virus/immunology ; Influenza Vaccines/genetics ; Influenza Vaccines/immunology ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; Madin Darby Canine Kidney Cells ; Mice ; MicroRNAs/genetics ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/prevention & control ; Recombination, Genetic ; Vaccines, Attenuated/genetics ; Vaccines, Attenuated/immunology
Chemical Substances	Influenza Vaccines ; MicroRNAs ; Vaccines, Attenuated
Language	English
Publishing date	2018--15
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.01741-17
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