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Article ; Online: Hantavirus entry: Perspectives and recent advances.

Mittler, Eva / Dieterle, Maria Eugenia / Kleinfelter, Lara M / Slough, Megan M / Chandran, Kartik / Jangra, Rohit K

2019 Volume 104, Page(s) 185–224

Abstract: Hantaviruses are important zoonotic pathogens of public health importance that are found on all continents except Antarctica and are associated with hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome (HPS) in ... ...

Abstract	Hantaviruses are important zoonotic pathogens of public health importance that are found on all continents except Antarctica and are associated with hemorrhagic fever with renal syndrome (HFRS) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. Despite the significant disease burden they cause, no FDA-approved specific therapeutics or vaccines exist against these lethal viruses. The lack of available interventions is largely due to an incomplete understanding of hantavirus pathogenesis and molecular mechanisms of virus replication, including cellular entry. Hantavirus Gn/Gc glycoproteins are the only viral proteins exposed on the surface of virions and are necessary and sufficient to orchestrate virus attachment and entry. In vitro studies have implicated integrins (β
MeSH term(s)	Biomedical Research/trends ; Hantavirus/physiology ; Host-Pathogen Interactions ; Protein Binding ; Receptors, Virus/metabolism ; Viral Envelope Proteins/metabolism ; Virus Attachment ; Virus Internalization
Chemical Substances	Receptors, Virus ; Viral Envelope Proteins
Language	English
Publishing date	2019-08-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	195-8
ISSN	1557-8399 ; 0065-3527
ISSN (online)	1557-8399
ISSN	0065-3527
DOI	10.1016/bs.aivir.2019.07.002
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Article ; Online: Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response.

Herman, Jonathan D / Wang, Chuangqi / Loos, Carolin / Yoon, Hyunah / Rivera, Johanna / Eugenia Dieterle, M / Haslwanter, Denise / Jangra, Rohit K / Bortz, Robert H / Bar, Katharine J / Julg, Boris / Chandran, Kartik / Lauffenburger, Douglas / Pirofski, Liise-Anne / Alter, Galit

Nature communications

2021 Volume 12, Issue 1, Page(s) 6853

Abstract: Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS- ... ...

Abstract	Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient's pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection.
MeSH term(s)	Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Blood Donors ; COVID-19/immunology ; COVID-19/therapy ; Humans ; Immunity ; Immunity, Humoral ; Immunization, Passive/methods ; Nucleocapsid/immunology ; Plasma/immunology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/immunology ; COVID-19 Serotherapy
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-11-25
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/s41467-021-27201-y
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Article ; Online: Genetic depletion studies inform receptor usage by virulent hantaviruses in human endothelial cells.

Dieterle, Maria Eugenia / Solà-Riera, Carles / Ye, Chunyan / Goodfellow, Samuel M / Mittler, Eva / Kasikci, Ezgi / Bradfute, Steven B / Klingström, Jonas / Jangra, Rohit K / Chandran, Kartik

eLife

2021 Volume 10

Abstract: Hantaviruses are RNA viruses with known epidemic threat and potential for emergence. Several rodent-borne hantaviruses cause zoonoses accompanied by severe illness and death. However, assessments of zoonotic risk and the development of countermeasures ... ...

Abstract	Hantaviruses are RNA viruses with known epidemic threat and potential for emergence. Several rodent-borne hantaviruses cause zoonoses accompanied by severe illness and death. However, assessments of zoonotic risk and the development of countermeasures are challenged by our limited knowledge of the molecular mechanisms of hantavirus infection, including the identities of cell entry receptors and their roles in influencing viral host range and virulence. Despite the long-standing presumption that β3/β1-containing integrins are the major hantavirus entry receptors, rigorous genetic loss-of-function evidence supporting their requirement, and that of decay-accelerating factor (DAF), is lacking. Here, we used CRISPR/Cas9 engineering to knockout candidate hantavirus receptors, singly and in combination, in a human endothelial cell line that recapitulates the properties of primary microvascular endothelial cells, the major targets of viral infection in humans. The loss of β3 integrin, β1 integrin, and/or DAF had little or no effect on entry by a large panel of hantaviruses. By contrast, loss of protocadherin-1, a recently identified entry receptor for some hantaviruses, substantially reduced hantavirus entry and infection. We conclude that major host molecules necessary for endothelial cell entry by PCDH1-independent hantaviruses remain to be discovered.
MeSH term(s)	Cell Line ; Endothelial Cells/virology ; Orthohantavirus/physiology ; Humans ; Receptors, Cell Surface/metabolism ; Viral Proteins/metabolism
Chemical Substances	Receptors, Cell Surface ; Viral Proteins
Language	English
Publishing date	2021-07-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.69708
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Article: Genomic surveillance of SARS-CoV-2 during the first year of the pandemic in the Bronx enabled clinical and epidemiological inference.

Fels, J Maximilian / Khan, Saad / Forster, Ryan / Skalina, Karin A / Sirichand, Surksha / Fox, Amy S / Bergman, Aviv / Mitchell, William B / Wolgast, Lucia R / Szymczak, Wendy / Bortz, Robert H / Dieterle, M Eugenia / Florez, Catalina / Haslwanter, Denise / Jangra, Rohit K / Laudermilch, Ethan / Wirchnianski, Ariel S / Barnhill, Jason / Goldman, David L /

Khine, Hnin / Goldstein, D Yitzchak / Daily, Johanna P / Chandran, Kartik / Kelly, Libusha

medRxiv : the preprint server for health sciences

2022

Abstract: The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of SARS-CoV-2 genomes across the Bronx from March-October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New ... ...

Abstract	The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of SARS-CoV-2 genomes across the Bronx from March-October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of variants, we found that while some became 'endemic' to the Bronx, other, novel variants rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic. One sentence summary: Temporally and geographically resolved sequencing of SARS-CoV-2 genotypes enabled surveillance of novel genotypes, identification of endemic viral variants, and clinical inferences, in the first wave of the COVID-19 pandemic in the Bronx.
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.02.08.21250641
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Article ; Online: Genomic surveillance of SARS-CoV-2 during the first year of the pandemic in the Bronx enabled clinical and epidemiological inference.

Fels, J Maximilian / Khan, Saad / Forster, Ryan / Skalina, Karin A / Sirichand, Surksha / Fox, Amy S / Bergman, Aviv / Mitchell, William B / Wolgast, Lucia R / Szymczak, Wendy A / Bortz, Robert H / Dieterle, M Eugenia / Florez, Catalina / Haslwanter, Denise / Jangra, Rohit K / Laudermilch, Ethan / Wirchnianski, Ariel S / Barnhill, Jason / Goldman, David L /

Khine, Hnin / Goldstein, D Yitzchak / Daily, Johanna P / Chandran, Kartik / Kelly, Libusha

Cold Spring Harbor molecular case studies

2022

Abstract: The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of 104 SARS-CoV-2 genomes across the Bronx from March October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New ...

Abstract	The Bronx was an early epicenter of the COVID-19 pandemic in the USA. We conducted temporal genomic surveillance of 104 SARS-CoV-2 genomes across the Bronx from March October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of mutations, we found that while some became 'endemic' to the Bronx, other, novel mutations rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic.
Language	English
Publishing date	2022-07-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a006211
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Article ; Online: Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response

Jonathan D. Herman / Chuangqi Wang / Carolin Loos / Hyunah Yoon / Johanna Rivera / M. Eugenia Dieterle / Denise Haslwanter / Rohit K. Jangra / Robert H. Bortz / Katharine J. Bar / Boris Julg / Kartik Chandran / Douglas Lauffenburger / Liise-anne Pirofski / Galit Alter

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 11

Abstract: Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find ... ...

Abstract	Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.
Keywords	Science ; Q
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic depletion studies inform receptor usage by virulent hantaviruses in human endothelial cells

Maria Eugenia Dieterle / Carles Solà-Riera / Chunyan Ye / Samuel M Goodfellow / Eva Mittler / Ezgi Kasikci / Steven B Bradfute / Jonas Klingström / Rohit K Jangra / Kartik Chandran

eLife, Vol

2021 Volume 10

Abstract	Hantaviruses are RNA viruses with known epidemic threat and potential for emergence. Several rodent-borne hantaviruses cause zoonoses accompanied by severe illness and death. However, assessments of zoonotic risk and the development of countermeasures are challenged by our limited knowledge of the molecular mechanisms of hantavirus infection, including the identities of cell entry receptors and their roles in influencing viral host range and virulence. Despite the long-standing presumption that β3/β1-containing integrins are the major hantavirus entry receptors, rigorous genetic loss-of-function evidence supporting their requirement, and that of decay-accelerating factor (DAF), is lacking. Here, we used CRISPR/Cas9 engineering to knockout candidate hantavirus receptors, singly and in combination, in a human endothelial cell line that recapitulates the properties of primary microvascular endothelial cells, the major targets of viral infection in humans. The loss of β3 integrin, β1 integrin, and/or DAF had little or no effect on entry by a large panel of hantaviruses. By contrast, loss of protocadherin-1, a recently identified entry receptor for some hantaviruses, substantially reduced hantavirus entry and infection. We conclude that major host molecules necessary for endothelial cell entry by PCDH1-independent hantaviruses remain to be discovered.
Keywords	Hantavirus ; receptor ; Endothelial cells ; CRISPR/Cas9 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Functional Antibodies in COVID-19 Convalescent Plasma.

Herman, Jonathan D / Wang, Chuangqi / Loos, Carolin / Yoon, Hyunah / Rivera, Johanna / Dieterle, M Eugenia / Haslwanter, Denise / Jangra, Rohit K / Bortz, Robert H / Bar, Katharine J / Julg, Boris / Chandran, Kartik / Lauffenburger, Douglas / Pirofski, Liise-Anne / Alter, Galit

medRxiv : the preprint server for health sciences

2021

Abstract: In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically ... ...

Abstract	In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 patients, many hospitalized COVID-19 patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 patients, that shaped the evolution of COVID-19 patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.
Language	English
Publishing date	2021-03-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.08.21253157
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Article ; Online: Longitudinally monitored immune biomarkers predict the timing of COVID-19 outcomes.

Lasso, Gorka / Khan, Saad / Allen, Stephanie A / Mariano, Margarette / Florez, Catalina / Orner, Erika P / Quiroz, Jose A / Quevedo, Gregory / Massimi, Aldo / Hegde, Aditi / Wirchnianski, Ariel S / Bortz, Robert H / Malonis, Ryan J / Georgiev, George I / Tong, Karen / Herrera, Natalia G / Morano, Nicholas C / Garforth, Scott J / Malaviya, Avinash /

Khokhar, Ahmed / Laudermilch, Ethan / Dieterle, M Eugenia / Fels, J Maximilian / Haslwanter, Denise / Jangra, Rohit K / Barnhill, Jason / Almo, Steven C / Chandran, Kartik / Lai, Jonathan R / Kelly, Libusha / Daily, Johanna P / Vergnolle, Olivia

PLoS computational biology

2022 Volume 18, Issue 1, Page(s) e1009778

Abstract: The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models ...

Abstract	The clinical outcome of SARS-CoV-2 infection varies widely between individuals. Machine learning models can support decision making in healthcare by assessing fatality risk in patients that do not yet show severe signs of COVID-19. Most predictive models rely on static demographic features and clinical values obtained upon hospitalization. However, time-dependent biomarkers associated with COVID-19 severity, such as antibody titers, can substantially contribute to the development of more accurate outcome models. Here we show that models trained on immune biomarkers, longitudinally monitored throughout hospitalization, predicted mortality and were more accurate than models based on demographic and clinical data upon hospital admission. Our best-performing predictive models were based on the temporal analysis of anti-SARS-CoV-2 Spike IgG titers, white blood cell (WBC), neutrophil and lymphocyte counts. These biomarkers, together with C-reactive protein and blood urea nitrogen levels, were found to correlate with severity of disease and mortality in a time-dependent manner. Shapley additive explanations of our model revealed the higher predictive value of day post-symptom onset (PSO) as hospitalization progresses and showed how immune biomarkers contribute to predict mortality. In sum, we demonstrate that the kinetics of immune biomarkers can inform clinical models to serve as a powerful monitoring tool for predicting fatality risk in hospitalized COVID-19 patients, underscoring the importance of contextualizing clinical parameters according to their time post-symptom onset.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Viral/blood ; Biomarkers/blood ; COVID-19/diagnosis ; COVID-19/epidemiology ; COVID-19/immunology ; COVID-19/therapy ; Computational Biology ; Diagnosis, Computer-Assisted ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Young Adult
Chemical Substances	Antibodies, Viral ; Biomarkers ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-01-18
Publishing country	United States
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	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1009778
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Article: A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition.

bioRxiv : the preprint server for biology

2020

Abstract: There is an urgent need for vaccines and therapeutics to prevent and treat COVID-19. Rapid SARS-CoV-2 countermeasure development is contingent on the availability of robust, scalable, and readily deployable surrogate viral assays to screen antiviral ... ...

Abstract	There is an urgent need for vaccines and therapeutics to prevent and treat COVID-19. Rapid SARS-CoV-2 countermeasure development is contingent on the availability of robust, scalable, and readily deployable surrogate viral assays to screen antiviral humoral responses, and define correlates of immune protection, and to down-select candidate antivirals. Here, we describe a highly infectious recombinant vesicular stomatitis virus bearing the SARS-CoV-2 spike glycoprotein S as its sole entry glycoprotein that closely resembles the authentic agent in its entry-related properties. We show that the neutralizing activities of a large panel of COVID-19 convalescent sera can be assessed in high-throughput fluorescent reporter assay with rVSV-SARS-CoV-2 S and that neutralization of the rVSV and authentic SARS-CoV-2 by spike-specific antibodies in these antisera is highly correlated. Our findings underscore the utility of rVSV-SARS-CoV-2 S for the development of spike-specific vaccines and therapeutics and for mechanistic studies of viral entry and its inhibition.
Keywords	covid19
Language	English
Publishing date	2020-05-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.05.20.105247
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