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  1. Article ; Online: Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy.

    Gress, Abigail R / Ronayne, Christine E / Thiede, Joshua M / Meyerholz, David K / Okurut, Samuel / Stumpf, Julia / Mathes, Tailor V / Ssebambulidde, Kenneth / Meya, David B / Cresswell, Fiona V / Boulware, David R / Bold, Tyler D

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 8423

    Abstract: After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77- ... ...

    Abstract After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFP
    MeSH term(s) Humans ; Mice ; Animals ; CD4-Positive T-Lymphocytes ; Receptors, OX40/agonists ; CD8-Positive T-Lymphocytes ; Immunotherapy ; Tuberculosis/therapy
    Chemical Substances Receptors, OX40
    Language English
    Publishing date 2023-12-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-44152-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.

    Cole, Malcolm S / Howe, Michael D / Buonomo, Joseph A / Sharma, Sachin / Lamont, Elise A / Brody, Scott I / Mishra, Neeraj K / Minato, Yusuke / Thiede, Joshua M / Baughn, Anthony D / Aldrich, Courtney C

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2022  Volume 28, Issue 51, Page(s) e202200995

    Abstract: ... therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb ... drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and ...

    Abstract Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA "warhead" as well as the β-lactam "promoiety" contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.
    MeSH term(s) Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis ; Pyrazinamide/analogs & derivatives ; Pyrazinamide/pharmacology ; Tuberculosis/drug therapy ; Tuberculosis/microbiology ; beta-Lactams/pharmacology
    Chemical Substances Antitubercular Agents ; beta-Lactams ; Pyrazinamide (2KNI5N06TI) ; pyrazinoic acid (2WB23298SP)
    Language English
    Publishing date 2022-07-27
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202200995
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pyrazinamide Susceptibility Is Driven by Activation of the SigE-Dependent Cell Envelope Stress Response in Mycobacterium tuberculosis.

    Thiede, Joshua M / Dillon, Nicholas A / Howe, Michael D / Aflakpui, Ranee / Modlin, Samuel J / Hoffner, Sven E / Valafar, Faramarz / Minato, Yusuke / Baughn, Anthony D

    mBio

    2022  Volume 13, Issue 1, Page(s) e0043921

    Abstract: Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined. In ... ...

    Abstract Pyrazinamide (PZA) plays a crucial role in first-line tuberculosis drug therapy. Unlike other antimicrobial agents, PZA is active against Mycobacterium tuberculosis only at low pH. The basis for this conditional drug susceptibility remains undefined. In this study, we utilized a genome-wide approach to interrogate potentiation of PZA action. We found that mutations in numerous genes involved in central metabolism as well as cell envelope maintenance and stress response are associated with PZA resistance. Further, we demonstrate that constitutive activation of the cell envelope stress response can drive PZA susceptibility independent of environmental pH. Consequently, exposure to peptidoglycan synthesis inhibitors, such as beta-lactams and d-cycloserine, potentiate PZA action through triggering this response. These findings illuminate a regulatory mechanism for conditional PZA susceptibility and reveal new avenues for enhancing potency of this important drug through targeting activation of the cell envelope stress response.
    MeSH term(s) Humans ; Pyrazinamide/therapeutic use ; Mycobacterium tuberculosis/genetics ; Amidohydrolases/metabolism ; Antitubercular Agents/pharmacology ; Tuberculosis/microbiology ; Mutation ; Microbial Sensitivity Tests
    Chemical Substances Pyrazinamide (2KNI5N06TI) ; Amidohydrolases (EC 3.5.-) ; Antitubercular Agents
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.00439-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Genomewide Assessment of Mycobacterium tuberculosis Conditionally Essential Metabolic Pathways.

    Minato, Yusuke / Gohl, Daryl M / Thiede, Joshua M / Chacón, Jeremy M / Harcombe, William R / Maruyama, Fumito / Baughn, Anthony D

    mSystems

    2019  Volume 4, Issue 4

    Abstract: A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes ... ...

    Abstract A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in
    Language English
    Publishing date 2019-06-25
    Publishing country United States
    Document type Journal Article
    ISSN 2379-5077
    ISSN 2379-5077
    DOI 10.1128/mSystems.00070-19
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Immune Profiling to Determine Early Disease Trajectories Associated With Coronavirus Disease 2019 Mortality Rate: A Substudy from the ACTT-1 Trial.

    Thiede, Joshua M / Gress, Abigail R / Libby, Samuel D / Ronayne, Christine E / Matchett, William E / Noren, Brooke / Billings, Joanne L / Menachery, Vineet D / Langlois, Ryan A / Kline, Susan / Bold, Tyler D

    The Journal of infectious diseases

    2021  Volume 223, Issue 8, Page(s) 1339–1344

    Abstract: Coronavirus disease 2019 (COVID-19) outcomes are linked to host immune responses and may be affected by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens ... ...

    Abstract Coronavirus disease 2019 (COVID-19) outcomes are linked to host immune responses and may be affected by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens from 19 hospitalized adults with COVID-19 randomized to treatment with remdesivir or placebo. We assessed severe acute respiratory syndrome coronavirus 2 antibody responses and identified cytokine signatures, using hierarchical clustering. We identified no clear immunologic trends attributable to remdesivir treatment. Seven participants were initially seronegative at study enrollment, and all 4 deaths occurred in this group with more recent symptom onset. We identified 3 dominant cytokine signatures, demonstrating different disease trajectories.
    MeSH term(s) Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/immunology ; Adenosine Monophosphate/therapeutic use ; Adult ; Alanine/analogs & derivatives ; Alanine/immunology ; Alanine/therapeutic use ; Antibodies, Viral/immunology ; Antiviral Agents/immunology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; COVID-19/immunology ; COVID-19/mortality ; COVID-19/virology ; Cytokines/immunology ; Female ; Humans ; Immunity/drug effects ; Immunity/immunology ; Male ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology
    Chemical Substances Antibodies, Viral ; Antiviral Agents ; Cytokines ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2021-01-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiab035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: SARS-CoV-2 neutralization and serology testing of COVID-19 convalescent plasma from donors with non-severe disease.

    Gniadek, Thomas J / Thiede, Joshua M / Matchett, William E / Gress, Abigail R / Pape, Kathryn A / Jenkins, Marc K / Menachery, Vineet D / Langlois, Ryan A / Bold, Tyler D

    bioRxiv : the preprint server for biology

    2020  

    Abstract: We determined the antigen binding activity of convalescent plasma units from 47 individuals with a history of non-severe COVID-19 using three clinical diagnostic serology assays (Beckman, DiaSorin, and Roche) with different SARS-CoV-2 targets. We ... ...

    Abstract We determined the antigen binding activity of convalescent plasma units from 47 individuals with a history of non-severe COVID-19 using three clinical diagnostic serology assays (Beckman, DiaSorin, and Roche) with different SARS-CoV-2 targets. We compared these results with functional neutralization activity using a fluorescent reporter strain of SARS-CoV-2 in a microwell assay. This revealed positive correlations of varying strength (Spearman r = 0.37-0.52) between binding and neutralization. Donors age 48-75 had the highest neutralization activity. Units in the highest tertile of binding activity for each assay were enriched (75-82%) for those with the highest levels of neutralization.
    Keywords covid19
    Language English
    Publishing date 2020-08-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2020.08.07.242271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium.

    Fiege, Jessica K / Thiede, Joshua M / Nanda, Hezkiel Arya / Matchett, William E / Moore, Patrick J / Montanari, Noe Rico / Thielen, Beth K / Daniel, Jerry / Stanley, Emma / Hunter, Ryan C / Menachery, Vineet D / Shen, Steven S / Bold, Tyler D / Langlois, Ryan A

    PLoS pathogens

    2021  Volume 17, Issue 1, Page(s) e1009292

    Abstract: The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, ... ...

    Abstract The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.
    MeSH term(s) Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Antiviral Agents/pharmacology ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/virology ; Epithelium/immunology ; Epithelium/virology ; Humans ; Interferons/genetics ; Interferons/immunology ; Interleukin-6/genetics ; Interleukin-6/immunology ; Lung/immunology ; Lung/virology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Viral Tropism/drug effects ; Virus Replication/drug effects ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Interleukin-6 ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Interferons (9008-11-1) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2021-01-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1009292
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: SARS-CoV-2 neutralization and serology testing of COVID-19 convalescent plasma from donors with nonsevere disease.

    Gniadek, Thomas J / Thiede, Joshua M / Matchett, William E / Gress, Abigail R / Pape, Kathryn A / Fiege, Jessica K / Jenkins, Marc K / Menachery, Vineet D / Langlois, Ryan A / Bold, Tyler D

    Transfusion

    2020  Volume 61, Issue 1, Page(s) 17–23

    Abstract: Background: The transfer of passive immunity with convalescent plasma is a promising strategy for treatment and prevention of COVID-19, but donors with a history of nonsevere disease are serologically heterogenous. The relationship between SARS-Cov-2 ... ...

    Abstract Background: The transfer of passive immunity with convalescent plasma is a promising strategy for treatment and prevention of COVID-19, but donors with a history of nonsevere disease are serologically heterogenous. The relationship between SARS-Cov-2 antigen-binding activity and neutralization activity in this population of donors has not been defined.
    Study design and methods: Convalescent plasma units from 47 individuals with a history of nonsevere COVID-19 were assessed for antigen-binding activity of using three clinical diagnostic serology assays (Beckman, DiaSorin, and Roche) with different SARS-CoV-2 targets. These results were compared with functional neutralization activity using a fluorescent reporter strain of SARS-CoV-2 in a microwell assay.
    Results: Positive correlations of varying strength (Spearman r = 0.37-0.52) between antigen binding and viral neutralization were identified. Donors age 48 to 75 years had the highest neutralization activity. Units in the highest tertile of binding activity for each assay were enriched (75%-82%) for those with the highest levels of neutralization.
    Conclusion: The strength of the relationship between antigen-binding activity and neutralization varies depending on the clinical assay used. Units in the highest tertile of binding activity for each assay are predominantly comprised of those with the greatest neutralization activity.
    MeSH term(s) Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; COVID-19/immunology ; COVID-19/therapy ; COVID-19 Serological Testing ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunization, Passive ; Immunoglobulin G/immunology ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Serologic Tests
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Immunoglobulin G
    Keywords covid19
    Language English
    Publishing date 2020-10-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 208417-x
    ISSN 1537-2995 ; 0041-1132
    ISSN (online) 1537-2995
    ISSN 0041-1132
    DOI 10.1111/trf.16101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity.

    Matchett, William E / Joag, Vineet / Stolley, J Michael / Shepherd, Frances K / Quarnstrom, Clare F / Mickelson, Clayton K / Wijeyesinghe, Sathi / Soerens, Andrew G / Becker, Samuel / Thiede, Joshua M / Weyu, Eyob / O'Flanagan, Stephen / Walter, Jennifer A / Vu, Michelle N / Menachery, Vineet D / Bold, Tyler D / Vezys, Vaiva / Jenkins, Marc K / Langlois, Ryan A /
    Masopust, David

    bioRxiv : the preprint server for biology

    2021  

    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing antibodies target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S- ...

    Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing antibodies target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with HAd5 expressing the nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and k18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral antigens, even if they are not a target of neutralizing antibodies, to broaden epitope coverage and immune effector mechanisms.
    Language English
    Publishing date 2021-04-27
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.04.26.441518
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium.

    Jessica K Fiege / Joshua M Thiede / Hezkiel Arya Nanda / William E Matchett / Patrick J Moore / Noe Rico Montanari / Beth K Thielen / Jerry Daniel / Emma Stanley / Ryan C Hunter / Vineet D Menachery / Steven S Shen / Tyler D Bold / Ryan A Langlois

    PLoS Pathogens, Vol 17, Iss 1, p e

    2021  Volume 1009292

    Abstract: The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, ... ...

    Abstract The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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