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  1. Article ; Online: Quantifying spatial dynamics of Mycobacterium tuberculosis infection of human macrophages using microfabricated patterns.

    Savulescu, Anca F / Peton, Nashied / Oosthuizen, Delia / Hazra, Rudranil / Rousseau, Robert P / Mhlanga, Musa M / Coussens, Anna K

    Cell reports methods

    2023  Volume 3, Issue 11, Page(s) 100640

    Abstract: Macrophages provide a first line of defense against invading pathogens, including the leading cause of bacterial mortality, Mycobacterium tuberculosis (Mtb). A challenge for quantitative characterization of host-pathogen processes in differentially ... ...

    Abstract Macrophages provide a first line of defense against invading pathogens, including the leading cause of bacterial mortality, Mycobacterium tuberculosis (Mtb). A challenge for quantitative characterization of host-pathogen processes in differentially polarized primary human monocyte-derived macrophages (MDMs) is their heterogeneous morphology. Here, we describe the use of microfabricated patterns that constrain the size and shape of cells, mimicking the physiological spatial confinement cells experience in tissues, to quantitatively characterize interactions during and after phagocytosis at the single-cell level at high resolution. Comparing pro-inflammatory (M1) and anti-inflammatory (M2) MDMs, we find interferon-γ stimulation increases the phagocytic contraction, while contraction and bacterial uptake decrease following silencing of phagocytosis regulator NHLRC2 or bacterial surface lipid removal. We identify host organelle position alterations within infected MDMs and differences in Mtb subcellular localization in line with M1 and M2 cellular polarity. Our approach can be adapted to study other host-pathogen interactions and coupled with downstream automated analytical approaches.
    MeSH term(s) Humans ; Macrophages ; Tuberculosis/microbiology ; Mycobacterium tuberculosis ; Phagocytosis ; Interferon-gamma
    Chemical Substances Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2023-11-13
    Publishing country United States
    Document type Journal Article
    ISSN 2667-2375
    ISSN (online) 2667-2375
    DOI 10.1016/j.crmeth.2023.100640
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Immunopathogenic overlap between COVID-19 and tuberculosis identified from transcriptomic meta-analysis and human macrophage infection.

    Sheerin, Dylan / Abhimanyu / Peton, Nashied / Vo, William / Allison, Cody Charles / Wang, Xutao / Johnson, W Evan / Coussens, Anna Kathleen

    iScience

    2022  Volume 25, Issue 6, Page(s) 104464

    Abstract: Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID- ... ...

    Abstract Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning disease severity, from whole blood, PBMCs, and BALF. 35 eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals across the spectrum of TB infection. Thirteen COVID-19 gene-signatures had significantly higher "COVID-19 risk scores" in active TB and latent TB progressors compared with non-progressors and uninfected controls (p<0·005), in three independent cohorts. Integrative single-cell-RNAseq analysis identified
    Language English
    Publishing date 2022-05-25
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.104464
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  3. Article ; Online: Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones.

    Basarab, Gregory S / Ghorpade, Sandeep / Gibhard, Liezl / Mueller, Rudolf / Njoroge, Mathew / Peton, Nashied / Govender, Preshendren / Massoudi, Lisa M / Robertson, Gregory Thomas / Lenaerts, Anne J / Boshoff, Helena Ingrid / Joerss, Douglas / Parish, Tanya / Durand-Reville, Thomas F / Perros, Manos / Singh, Vinayak / Chibale, Kelly

    Antimicrobial agents and chemotherapy

    2022  Volume 66, Issue 4, Page(s) e0219221

    Abstract: Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves ... ...

    Abstract Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg
    MeSH term(s) DNA Gyrase/genetics ; Fluoroquinolones/pharmacology ; Fluoroquinolones/therapeutic use ; Humans ; Mycobacterium tuberculosis ; Topoisomerase II Inhibitors/pharmacology ; Tuberculosis/drug therapy
    Chemical Substances Fluoroquinolones ; Topoisomerase II Inhibitors ; DNA Gyrase (EC 5.99.1.3)
    Language English
    Publishing date 2022-03-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/aac.02192-21
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  4. Article ; Online: Voltage-gated T-type calcium channel blockers reduce apoptotic body-mediated SARS-CoV-2 cell-to-cell spread and subsequent cytokine storm

    Phan, Thanh Kha / Sheerin, Dylan / Shi, Bo / Dayton, Merle / Mackiewicz, Liana / Ozkocak, Dilara C / Atkin-Smith, Georgia / Peton, Nashied / Audi, Omar / Tixeira, Rochelle / Ashdown, George / Davidson, Kathryn C / Doerflinger, Marcel / Coussens, Anna K. / Poon, Ivan K. H.

    bioRxiv

    Abstract: SARS-CoV-2 typically utilises host angiotensin-converting enzyme 2 (ACE2) as a cellular surface receptor and host serine protease TMPRSS2 for the proteolytic activation of viral spike protein enabling viral entry. Although macrophages express low levels ... ...

    Abstract SARS-CoV-2 typically utilises host angiotensin-converting enzyme 2 (ACE2) as a cellular surface receptor and host serine protease TMPRSS2 for the proteolytic activation of viral spike protein enabling viral entry. Although macrophages express low levels of ACE2, they are often found positive for SARS-CoV-2 in autopsied lungs from COVID-19 patients. As viral-induced macrophage inflammation and overwhelming cytokine release are key immunopathological events that drives exacerbated tissue damage in severe COVID-19 patients, insights into the entry of SARS-CoV-2 into macrophages are therefore critical to understand COVID-19 pathogenesis and devise novel COVID-19 therapies. Mounting evidence suggest that COVID-19 pathogenesis is associated with apoptosis, a type of programmed cell death that often leads to the release of numerous large extracellular vesicles (EVs) called apoptotic bodies (ApoBDs). Here, we showed that ApoBDs derived from SARS-CoV-2-infected cells carry viral antigens and infectious virions. Human monocyte-derived macrophages readily efferocytosed SARS-CoV-2-induced ApoBDs, resulting in SARS-CoV-2 entry and pro-inflammatory responses. To target this novel ApoBD-mediated viral entry process, we screened for ApoBD formation inhibitors and discovered that T-type voltage-gated calcium channel (T-channel) blockers can inhibit SARS-CoV-2-induced ApoBD formation. Mechanistically, T-channel blockers impaired the extracellular calcium influxes required for ApoBD biogenesis. Importantly, blockade of ApoBD formation by T-channel blockers were able to limit viral dissemination and virus-induced macrophage inflammation in vitro and in a pre-clinical mouse model of severe COVID-19. Our discovery of the ApoBD-efferocytosis-mediated viral entry reveals a novel route for SARS-CoV-2 infection and cytokine storm induction, expanding our understanding of COVID-19 pathogenesis and offering new therapeutic avenues for infectious diseases.
    Keywords covid19
    Language English
    Publishing date 2023-11-06
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.11.03.565419
    Database COVID19

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  5. Article ; Online: Recent progress in understanding immune activation in the pathogenesis in HIV-tuberculosis co-infection.

    du Bruyn, Elsa / Peton, Nashied / Esmail, Hanif / Howlett, Patrick J / Coussens, Anna K / Wilkinson, Robert J

    Current opinion in HIV and AIDS

    2018  Volume 13, Issue 6, Page(s) 455–461

    Abstract: Purpose of review: Tuberculosis is the leading infectious cause of death worldwide, and HIV-1 the best recognized risk factor for active TB. This review focuses on immune complex formation; the interplay of type I and II interferon signaling; and T-cell ...

    Abstract Purpose of review: Tuberculosis is the leading infectious cause of death worldwide, and HIV-1 the best recognized risk factor for active TB. This review focuses on immune complex formation; the interplay of type I and II interferon signaling; and T-cell activation in HIV-TB pathogenesis.
    Recent findings: Circulating immune complexes and complement, and Fcγ signaling in whole blood act as early markers of TB disease in HIV-1-infected persons. HIV-1 is associated with a type I interferon response in whole blood, reducing the specificity of TB biomarkers dependent on type I and II interferon genes. Type I and type II interferons are implicated in both protection and TB disease, a protective outcome may depend on modulating these pathways. Whilst M. tuberculosis-specific CD4 T cells are preferentially depleted during HIV-1 infection, activation markers on M. tuberculosis-specific CD4 T cells, in particular HLA-DR, reflect immune activation and have promise as biomarkers of M. tuberculosis disease activity in individuals with HIV-1.
    Summary: TB pathogenesis in HIV-1 involves a complex interaction of underlying activation of both the innate and adaptive immune systems. Further research is required to understand whether biomarkers of activation could be used to predict or quantify TB disease in the context of HIV-1 infection.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/immunology ; Coinfection/immunology ; Coinfection/microbiology ; Coinfection/virology ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/physiology ; Humans ; Mycobacterium tuberculosis/physiology ; Tuberculosis/immunology ; Tuberculosis/microbiology
    Language English
    Publishing date 2018-10-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2502511-9
    ISSN 1746-6318 ; 1746-630X
    ISSN (online) 1746-6318
    ISSN 1746-630X
    DOI 10.1097/COH.0000000000000501
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6812: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: A molecular physiological review of vegetative desiccation tolerance in the resurrection plant Xerophyta viscosa (Baker)

    Farrant, Jill M / Cooper, Keren / Hilgart, Amelia / Abdalla, Kamal O / Bentley, Joanne / Thomson, Jennifer A / Dace, Halford J. W / Peton, Nashied / Mundree, Sagadevan G / Rafudeen, Mohamed S

    Planta. 2015 Aug., v. 242, no. 2

    2015  

    Abstract: MAIN CONCLUSION : Provides a first comprehensive review of integrated physiological and molecular aspects of desiccation tolerance Xerophyta viscosa . A synopsis of biotechnological studies being undertaken to improve drought tolerance in maize is given. ...

    Abstract MAIN CONCLUSION : Provides a first comprehensive review of integrated physiological and molecular aspects of desiccation tolerance Xerophyta viscosa . A synopsis of biotechnological studies being undertaken to improve drought tolerance in maize is given. Xerophyta viscosa (Baker) is a monocotyledonous resurrection plant from the family Vellociacea that occurs in summer-rainfall areas of South Africa, Lesotho and Swaziland. It inhabits rocky terrain in exposed grasslands and frequently experiences periods of water deficit. Being a resurrection plant it tolerates the loss of 95 % of total cellular water, regaining full metabolic competency within 3 days of rehydration. In this paper, we review some of the molecular and physiological adaptations that occur during various stages of dehydration of X. viscosa, these being functionally grouped into early and late responses, which might be relevant to the attainment of desiccation tolerance. During early drying (to 55 % RWC) photosynthesis is shut down, there is increased presence and activity of housekeeping antioxidants and a redirection of metabolism to the increased formation of sucrose and raffinose family oligosaccharides. Other metabolic shifts suggest water replacement in vacuoles proposed to facilitate mechanical stabilization. Some regulatory processes observed include increased presence of a linker histone H1 variant, a Type 2C protein phosphatase, a calmodulin- and an ERD15-like protein. During the late stages of drying (to 10 % RWC) there was increased expression of several proteins involved in signal transduction, and retroelements speculated to be instrumental in gene silencing. There was induction of antioxidants not typically found in desiccation-sensitive systems, classical stress-associated proteins (HSP and LEAs), proteins involved in structural stabilization and those associated with changes in various metabolite pools during drying. Metabolites accumulated in this stage are proposed, inter alia, to facilitate subcellular stabilization by vitrification process which can include glass- and ionic liquid formation.
    Keywords antioxidants ; corn ; drought tolerance ; drying ; gene silencing ; grasslands ; histones ; ionic liquids ; metabolites ; photosynthesis ; raffinose ; rehydration ; retrotransposons ; signal transduction ; sucrose ; vacuoles ; vitrification ; Lesotho ; South Africa ; Swaziland
    Language English
    Dates of publication 2015-08
    Size p. 407-426.
    Publishing place Springer Berlin Heidelberg
    Document type Article
    ZDB-ID 208909-9
    ISSN 1432-2048 ; 0032-0935
    ISSN (online) 1432-2048
    ISSN 0032-0935
    DOI 10.1007/s00425-015-2320-6
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  7. Article ; Online: A molecular physiological review of vegetative desiccation tolerance in the resurrection plant Xerophyta viscosa (Baker).

    Farrant, Jill M / Cooper, Keren / Hilgart, Amelia / Abdalla, Kamal O / Bentley, Joanne / Thomson, Jennifer A / Dace, Halford J W / Peton, Nashied / Mundree, Sagadevan G / Rafudeen, Mohamed S

    Planta

    2015  Volume 242, Issue 2, Page(s) 407–426

    Abstract: Main conclusion: Provides a first comprehensive review of integrated physiological and molecular aspects of desiccation tolerance Xerophyta viscosa. A synopsis of biotechnological studies being undertaken to improve drought tolerance in maize is given. ... ...

    Abstract Main conclusion: Provides a first comprehensive review of integrated physiological and molecular aspects of desiccation tolerance Xerophyta viscosa. A synopsis of biotechnological studies being undertaken to improve drought tolerance in maize is given. Xerophyta viscosa (Baker) is a monocotyledonous resurrection plant from the family Vellociacea that occurs in summer-rainfall areas of South Africa, Lesotho and Swaziland. It inhabits rocky terrain in exposed grasslands and frequently experiences periods of water deficit. Being a resurrection plant it tolerates the loss of 95% of total cellular water, regaining full metabolic competency within 3 days of rehydration. In this paper, we review some of the molecular and physiological adaptations that occur during various stages of dehydration of X. viscosa, these being functionally grouped into early and late responses, which might be relevant to the attainment of desiccation tolerance. During early drying (to 55% RWC) photosynthesis is shut down, there is increased presence and activity of housekeeping antioxidants and a redirection of metabolism to the increased formation of sucrose and raffinose family oligosaccharides. Other metabolic shifts suggest water replacement in vacuoles proposed to facilitate mechanical stabilization. Some regulatory processes observed include increased presence of a linker histone H1 variant, a Type 2C protein phosphatase, a calmodulin- and an ERD15-like protein. During the late stages of drying (to 10% RWC) there was increased expression of several proteins involved in signal transduction, and retroelements speculated to be instrumental in gene silencing. There was induction of antioxidants not typically found in desiccation-sensitive systems, classical stress-associated proteins (HSP and LEAs), proteins involved in structural stabilization and those associated with changes in various metabolite pools during drying. Metabolites accumulated in this stage are proposed, inter alia, to facilitate subcellular stabilization by vitrification process which can include glass- and ionic liquid formation.
    MeSH term(s) Adaptation, Physiological ; Biotechnology ; Craterostigma/anatomy & histology ; Craterostigma/classification ; Craterostigma/genetics ; Craterostigma/physiology ; Desiccation ; Oxidative Stress ; Stress, Physiological
    Language English
    Publishing date 2015-05-22
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 208909-9
    ISSN 1432-2048 ; 0032-0935 ; 1866-2749
    ISSN (online) 1432-2048
    ISSN 0032-0935 ; 1866-2749
    DOI 10.1007/s00425-015-2320-6
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