LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 21

Search options

  1. Article ; Online: Nonrespiratory sites of influenza-associated disease: mechanisms and experimental systems for continued study.

    Froggatt, Heather M / Heaton, Nicholas S

    The FEBS journal

    2022  Volume 289, Issue 14, Page(s) 4038–4060

    Abstract: The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are ... ...

    Abstract The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are not similarly tissue restricted. As such, circulating inflammatory mediators, as well as the resulting activated immune cells, can induce damage throughout the body, particularly in individuals with underlying conditions. As a result, more holistic experimental approaches are required to fully understand the pathogenesis and scope of influenza virus-induced disease. This review summarizes what is known about some of the most well-appreciated nonrespiratory tract sites of influenza virus-induced disease, including neurological, cardiovascular, gastrointestinal, muscular and fetal developmental phenotypes. In the context of this discussion, we describe the in vivo experimental systems currently being used to study nonrespiratory symptoms. Finally, we highlight important future questions and potential models that can be used for a more complete understanding of influenza virus-induced disease.
    MeSH term(s) Cytokines ; Humans ; Inflammation Mediators ; Influenza, Human/complications ; Lung ; Orthomyxoviridae Infections ; Virus Replication
    Chemical Substances Cytokines ; Inflammation Mediators
    Language English
    Publishing date 2022-02-07
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16363
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  2. Article: Nonrespiratory sites of influenza‐associated disease: mechanisms and experimental systems for continued study

    Froggatt, Heather M. / Heaton, Nicholas S.

    FEBS journal. 2022 July, v. 289, no. 14

    2022  

    Abstract: The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are ... ...

    Abstract The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are not similarly tissue restricted. As such, circulating inflammatory mediators, as well as the resulting activated immune cells, can induce damage throughout the body, particularly in individuals with underlying conditions. As a result, more holistic experimental approaches are required to fully understand the pathogenesis and scope of influenza virus‐induced disease. This review summarizes what is known about some of the most well‐appreciated nonrespiratory tract sites of influenza virus‐induced disease, including neurological, cardiovascular, gastrointestinal, muscular and fetal developmental phenotypes. In the context of this discussion, we describe the in vivo experimental systems currently being used to study nonrespiratory symptoms. Finally, we highlight important future questions and potential models that can be used for a more complete understanding of influenza virus‐induced disease.
    Keywords chemokines ; gastrointestinal system ; human influenza ; pathogenesis ; respiratory system
    Language English
    Dates of publication 2022-07
    Size p. 4038-4060.
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note REVIEW
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16363
    Database NAL-Catalogue (AGRICOLA)

    More links

    Kategorien

  3. Article ; Online: Development of a Fluorescence-Based, High-Throughput SARS-CoV-2 3CL

    Froggatt, Heather M / Heaton, Brook E / Heaton, Nicholas S

    Journal of virology

    2020  Volume 94, Issue 22

    Abstract: In late 2019, a human coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, likely from a zoonotic reservoir. This virus causes COVID-19, has infected millions of people, and has led to hundreds of thousands of ... ...

    Abstract In late 2019, a human coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, likely from a zoonotic reservoir. This virus causes COVID-19, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best interventions to control and ultimately stop the pandemic are prophylactic vaccines, antiviral therapeutics are important to limit morbidity and mortality in those already infected. At this time, only one FDA-approved anti-SARS-CoV-2 antiviral drug, remdesivir, is available, and unfortunately, its efficacy appears to be limited. Thus, the identification of new and efficacious antivirals is of the highest importance. In order to facilitate rapid drug discovery, flexible, sensitive, and high-throughput screening methods are required. With respect to drug targets, most attention is focused on either the viral RNA-dependent RNA polymerase or the main viral protease, 3CL
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Betacoronavirus/chemistry ; COVID-19 ; Chlorocebus aethiops ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Cysteine Endopeptidases ; Drug Discovery ; High-Throughput Screening Assays/methods ; Humans ; Microscopy, Fluorescence/methods ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/virology ; Protease Inhibitors/pharmacology ; SARS-CoV-2 ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors
    Chemical Substances Antiviral Agents ; Protease Inhibitors ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Keywords covid19
    Language English
    Publishing date 2020-10-27
    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.01265-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  4. Article ; Online: ETV7 limits antiviral gene expression and control of influenza viruses.

    Froggatt, Heather M / Harding, Alfred T / Chaparian, Ryan R / Heaton, Nicholas S

    Science signaling

    2021  Volume 14, Issue 691

    Abstract: The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict ...

    Abstract The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict viral spread, whereas excessive ISG activation can result in IFN-related pathologies. Although both positive and negative regulatory factors control the magnitude and duration of IFN signaling, it is also appreciated that several ISGs regulate aspects of the IFN response themselves. In this study, we performed a CRISPR activation screen to identify previously unknown regulators of the type I IFN response. We identified the strongly induced ISG encoding ETS variant transcription factor 7 (ETV7) as a negative regulator of the type I IFN response. However, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 preferentially targeted a subset of antiviral ISGs that were particularly important for IFN-mediated control of influenza viruses. Together, our data assign a function for ETV7 as an IFN response regulator and also identify ETV7 as a potential therapeutic target to increase innate antiviral responses and enhance IFN-based antiviral therapies.
    MeSH term(s) Antiviral Restriction Factors/immunology ; Gene Expression ; Immunity, Innate ; Interferon Type I/immunology ; Orthomyxoviridae ; Proto-Oncogene Proteins c-ets/genetics
    Chemical Substances Antiviral Restriction Factors ; Interferon Type I ; Proto-Oncogene Proteins c-ets
    Language English
    Publishing date 2021-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.abe1194
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  5. Article ; Online: A low-background, fluorescent assay to evaluate inhibitors of diverse viral proteases.

    Leonard, Rebecca A / Rao, Vishwas N / Bartlett, Alexandria / Froggatt, Heather M / Luftig, Micah A / Heaton, Brook E / Heaton, Nicholas S

    Journal of virology

    2023  Volume 97, Issue 8, Page(s) e0059723

    Abstract: ... the SARS-CoV-2 M ...

    Abstract Multiple coronaviruses (CoVs) can cause respiratory diseases in humans. While prophylactic vaccines designed to prevent infection are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), incomplete vaccine efficacy, vaccine hesitancy, and the threat of other pathogenic CoVs for which vaccines do not exist have highlighted the need for effective antiviral therapies. While antiviral compounds targeting the viral polymerase and protease are already in clinical use, their sensitivity to potential resistance mutations as well as their breadth against the full range of human and preemergent CoVs remain incompletely defined. To begin to fill that gap in knowledge, we report here the development of an improved, noninfectious, cell-based fluorescent assay with high sensitivity and low background that reports on the activity of viral proteases, which are key drug targets. We demonstrate that the assay is compatible with not only the SARS-CoV-2 M
    MeSH term(s) Humans ; Antiviral Agents/pharmacology ; COVID-19 ; Protease Inhibitors/pharmacology ; SARS-CoV-2 ; Viral Proteases
    Chemical Substances Antiviral Agents ; ensitrelvir (PX665RAA3H) ; Protease Inhibitors ; Viral Proteases (EC 3.4.-) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; nirmatrelvir (7R9A5P7H32)
    Language English
    Publishing date 2023-08-14
    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.00597-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  6. Article ; Online: GPER1 is required to protect fetal health from maternal inflammation.

    Harding, Alfred T / Goff, Marisa A / Froggatt, Heather M / Lim, Jean K / Heaton, Nicholas S

    Science (New York, N.Y.)

    2021  Volume 371, Issue 6526, Page(s) 271–276

    Abstract: Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN ... ...

    Abstract Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN generated during maternal infections only rarely causes fetal developmental defects. Here, we report that activation of the guanine nucleotide-binding protein-coupled estrogen receptor 1 (GPER1) during pregnancy is both necessary and sufficient to suppress IFN signaling and does so disproportionately in reproductive and fetal tissues. Inactivation of GPER1 in mice halted fetal development and promoted fetal demise, but only in the context of maternal inflammation. Thus, GPER1 is a central regulator of IFN signaling during pregnancy that allows dynamic antiviral responses in maternal tissues while also preserving fetal health.
    MeSH term(s) Animals ; Benzodioxoles/pharmacology ; CRISPR-Cas Systems ; Female ; Fetal Diseases/immunology ; Fetal Diseases/virology ; Fetus/immunology ; Fetus/virology ; Humans ; Inflammation/immunology ; Influenza A virus/immunology ; Influenza, Human/immunology ; Interferon Type I/immunology ; Maternal-Fetal Exchange/immunology ; Mice ; Mice, Inbred C57BL ; Placenta/immunology ; Placenta/virology ; Pregnancy ; Pregnancy Complications, Infectious/immunology ; Quinolines/pharmacology ; Receptors, Estrogen/antagonists & inhibitors ; Receptors, Estrogen/metabolism ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/metabolism
    Chemical Substances 4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline ; Benzodioxoles ; GPER1 protein, human ; GPER1 protein, mouse ; Interferon Type I ; Quinolines ; Receptors, Estrogen ; Receptors, G-Protein-Coupled
    Language English
    Publishing date 2021-01-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aba9001
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  7. Article ; Online: Development of a fluorescence based, high-throughput SARS-CoV-2 3CLpro reporter assay

    Froggatt, Heather M / Heaton, Brook E / Heaton, Nicholas S

    bioRxiv

    Abstract: In late 2019 a human coronavirus, now known as SARS-CoV-2, emerged, likely from a zoonotic reservoir. This virus causes COVID-19 disease, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best ... ...

    Abstract In late 2019 a human coronavirus, now known as SARS-CoV-2, emerged, likely from a zoonotic reservoir. This virus causes COVID-19 disease, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best interventions to control and ultimately stop the pandemic are prophylactic vaccines, antiviral therapeutics are important to limit morbidity and mortality in those already infected. At this time, only one FDA approved anti-SARS-CoV-2 antiviral drug, remdesivir, is available and unfortunately, its efficacy appears to be limited. Thus, the identification of new and efficacious antivirals is of highest importance. In order to facilitate rapid drug discovery, flexible, sensitive, and high-throughput screening methods are required. With respect to drug targets, most attention is focused on either the viral RNA-dependent RNA polymerase or the main viral protease, 3CLpro. 3CLpro is an attractive target for antiviral therapeutics as it is essential for processing newly translated viral proteins, and the viral lifecycle cannot be completed without protease activity. In this work, we present a new assay to identify inhibitors of the SARS-CoV-2 main protease, 3CLpro. Our reporter is based on a GFP-derived protein that only fluoresces after cleavage by 3CLpro. This experimentally optimized reporter assay allows for antiviral drug screening in human cell culture at biosafety level-2 (BSL2) with high-throughput compatible protocols. Using this screening approach in combination with existing drug libraries may lead to the rapid identification of novel antivirals to suppress SARS-CoV-2 replication and spread.
    Keywords covid19
    Language English
    Publishing date 2020-06-24
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.06.24.169565
    Database COVID19

    Kategorien

  8. Article ; Online: Development of a fluorescence based, high-throughput SARS-CoV-2 3CLpro reporter assay

    Froggatt, Heather M. / Heaton, Brook E. / Heaton, Nicholas S.

    bioRxiv

    Abstract: In late 2019 a human coronavirus, now known as SARS-CoV-2, emerged, likely from a zoonotic reservoir. This virus causes COVID-19 disease, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best ... ...

    Abstract In late 2019 a human coronavirus, now known as SARS-CoV-2, emerged, likely from a zoonotic reservoir. This virus causes COVID-19 disease, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best interventions to control and ultimately stop the pandemic are prophylactic vaccines, antiviral therapeutics are important to limit morbidity and mortality in those already infected. At this time, only one FDA approved anti-SARS-CoV-2 antiviral drug, remdesivir, is available and unfortunately, its efficacy appears to be limited. Thus, the identification of new and efficacious antivirals is of highest importance. In order to facilitate rapid drug discovery, flexible, sensitive, and high-throughput screening methods are required. With respect to drug targets, most attention is focused on either the viral RNA-dependent RNA polymerase or the main viral protease, 3CLpro. 3CLpro is an attractive target for antiviral therapeutics as it is essential for processing newly translated viral proteins, and the viral lifecycle cannot be completed without protease activity. In this work, we present a new assay to identify inhibitors of the SARS-CoV-2 main protease, 3CLpro. Our reporter is based on a GFP-derived protein that only fluoresces after cleavage by 3CLpro. This experimentally optimized reporter assay allows for antiviral drug screening in human cell culture at biosafety level-2 (BSL2) with high-throughput compatible protocols. Using this screening approach in combination with existing drug libraries may lead to the rapid identification of novel antivirals to suppress SARS-CoV-2 replication and spread. IMPORTANCE The COVID-19 pandemic has already led to more than 400,000 deaths and innumerable changes to daily life worldwide. Along with development of a vaccine, identification of effective antivirals to treat infected patients is of the highest importance. However, rapid drug discovery requires efficient methods to identify novel compounds that can inhibit the virus. In this work, we present a method for identifying inhibitors of the SARS-CoV-2 main protease, 3CLpro. This reporter-based assay allows for antiviral drug screening in human cell culture at biosafety level-2 (BSL2) with high-throughput compatible sample processing and analysis. This assay may help identify novel antivirals to control the COVID-19 pandemic.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.06.24.169565
    Database COVID19

    Kategorien

  9. Article ; Online: Development of a Fluorescence-Based, High-Throughput SARS-CoV-2 3CLpro Reporter Assay

    Froggatt, Heather M. / Heaton, Brook E. / Heaton, Nicholas S.

    Journal of Virology

    2020  Volume 94, Issue 22

    Abstract: ABSTRACT In late 2019, a human coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, likely from a zoonotic reservoir. This virus causes COVID-19, has infected millions of people, and has led to hundreds of ... ...

    Abstract ABSTRACT In late 2019, a human coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, likely from a zoonotic reservoir. This virus causes COVID-19, has infected millions of people, and has led to hundreds of thousands of deaths across the globe. While the best interventions to control and ultimately stop the pandemic are prophylactic vaccines, antiviral therapeutics are important to limit morbidity and mortality in those already infected. At this time, only one FDA-approved anti-SARS-CoV-2 antiviral drug, remdesivir, is available, and unfortunately, its efficacy appears to be limited. Thus, the identification of new and efficacious antivirals is of the highest importance. In order to facilitate rapid drug discovery, flexible, sensitive, and high-throughput screening methods are required. With respect to drug targets, most attention is focused on either the viral RNA-dependent RNA polymerase or the main viral protease, 3CL pro . 3CL pro is an attractive target for antiviral therapeutics, as it is essential for processing newly translated viral proteins and the viral life cycle cannot be completed without protease activity. In this work, we report a new assay to identify inhibitors of 3CL pro . Our reporter is based on a green fluorescent protein (GFP)-derived protein that fluoresces only after cleavage by 3CL pro . This experimentally optimized reporter assay allows for antiviral drug screening in human cell culture at biosafety level 2 (BSL2) with high-throughput compatible protocols. Using this screening approach in combination with existing drug libraries may lead to the rapid identification of novel antivirals to suppress SARS-CoV-2 replication and spread. IMPORTANCE The COVID-19 pandemic has already led to more than 700,000 deaths and innumerable changes to daily life worldwide. Along with development of a vaccine, identification of effective antivirals to treat infected patients is of the highest importance. However, rapid drug discovery requires efficient methods to identify novel compounds that can inhibit the virus. In this work, we present a method for identifying inhibitors of the SARS-CoV-2 main protease, 3CL pro . This reporter-based assay allows for antiviral drug screening in human cell culture at biosafety level 2 (BSL2) with high-throughput compatible sample processing and analysis. This assay may help identify novel antivirals to control the COVID-19 pandemic.
    Keywords Immunology ; Insect Science ; Microbiology ; Virology ; covid19
    Language English
    Publisher American Society for Microbiology
    Publishing country us
    Document type Article ; Online
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01265-20
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    More links

    Kategorien

  10. Article ; Online: Influenza A virus segments five and six can harbor artificial introns allowing expanded coding capacity.

    Froggatt, Heather M / Burke, Kaitlyn N / Chaparian, Ryan R / Miranda, Hector A / Zhu, Xinyu / Chambers, Benjamin S / Heaton, Nicholas S

    PLoS pathogens

    2021  Volume 17, Issue 9, Page(s) e1009951

    Abstract: Influenza A viruses encode their genomes across eight, negative sense RNA segments. The six largest segments produce mRNA transcripts that do not generally splice; however, the two smallest segments are actively spliced to produce the essential viral ... ...

    Abstract Influenza A viruses encode their genomes across eight, negative sense RNA segments. The six largest segments produce mRNA transcripts that do not generally splice; however, the two smallest segments are actively spliced to produce the essential viral proteins NEP and M2. Thus, viral utilization of RNA splicing effectively expands the viral coding capacity without increasing the number of genomic segments. As a first step towards understanding why splicing is not more broadly utilized across genomic segments, we designed and inserted an artificial intron into the normally nonsplicing NA segment. This insertion was tolerated and, although viral mRNAs were incompletely spliced, we observed only minor effects on viral fitness. To take advantage of the unspliced viral RNAs, we encoded a reporter luciferase gene in frame with the viral ORF such that when the intron was not removed the reporter protein would be produced. This approach, which we also show can be applied to the NP encoding segment and in different viral genetic backgrounds, led to high levels of reporter protein expression with minimal effects on the kinetics of viral replication or the ability to cause disease in experimentally infected animals. These data together show that the influenza viral genome is more tolerant of splicing than previously appreciated and this knowledge can be leveraged to develop viral genetic platforms with utility for biotechnology applications.
    MeSH term(s) Animals ; Humans ; Influenza A virus/genetics ; Introns/genetics ; RNA Splicing/genetics ; RNA, Viral/genetics
    Chemical Substances RNA, Viral
    Language English
    Publishing date 2021-09-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1009951
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top