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  1. Article ; Online: BCG mediated protection of the lung against experimental SARS-CoV-2 infection.

    Hilligan, Kerry L / Namasivayam, Sivaranjani / Sher, Alan

    Frontiers in immunology

    2023  Volume 14, Page(s) 1232764

    Abstract: The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent ... ...

    Abstract The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent epidemiologic studies and clinical trials have largely failed to support this hypothesis. Furthermore, in small animal model studies all investigators have failed to observe resistance to viral challenge in response to BCG immunization by the conventional and clinically acceptable intradermal or subcutaneous routes. Nevertheless, BCG administered by the intravenous (IV) route has been shown to strongly protect both hamsters and mice against SCV2 infection and disease. In this Perspective, we review the current data on the effects of BCG vaccination on resistance to COVID-19 as well as summarize recent work in rodent models on the mechanisms by which IV administered BCG promotes resistance to the virus and discuss the translational implications of these findings.
    MeSH term(s) Cricetinae ; Animals ; Mice ; COVID-19/prevention & control ; SARS-CoV-2 ; BCG Vaccine ; Thorax ; Lung
    Chemical Substances BCG Vaccine
    Language English
    Publishing date 2023-09-08
    Publishing country Switzerland
    Document type Review ; Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1232764
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Memory-phenotype CD4+ T cells: a naturally arising T lymphocyte population possessing innate immune function.

    Kawabe, Takeshi / Sher, Alan

    International immunology

    2021  Volume 34, Issue 4, Page(s) 189–196

    Abstract: In conventional adaptive immune responses, upon recognition of foreign antigens, naive CD4+ T lymphocytes are activated to differentiate into effector/memory cells. In addition, emerging evidence suggests that in the steady state, naive CD4+ T cells ... ...

    Abstract In conventional adaptive immune responses, upon recognition of foreign antigens, naive CD4+ T lymphocytes are activated to differentiate into effector/memory cells. In addition, emerging evidence suggests that in the steady state, naive CD4+ T cells spontaneously proliferate in response to self-antigens to acquire a memory phenotype (MP) through homeostatic proliferation. This expansion is particularly profound in lymphopenic environments but also occurs in lymphoreplete, normal conditions. The 'MP T lymphocytes' generated in this manner are maintained by rapid proliferation in the periphery and they tonically differentiate into T-bet-expressing 'MP1' cells. Such MP1 CD4+ T lymphocytes can exert innate effector function, producing IFN-γ in response to IL-12 in the absence of antigen recognition, thereby contributing to host defense. In this review, we will discuss our current understanding of how MP T lymphocytes are generated and persist in steady-state conditions, their populational heterogeneity as well as the evidence for their effector function. We will also compare these properties with those of a similar population of innate memory cells previously identified in the CD8+ T lymphocyte lineage.
    MeSH term(s) CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Humans ; Immunologic Memory ; Lymphocyte Activation ; Lymphopenia ; Phenotype
    Language English
    Publishing date 2021-12-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1013745-2
    ISSN 1460-2377 ; 0953-8178
    ISSN (online) 1460-2377
    ISSN 0953-8178
    DOI 10.1093/intimm/dxab108
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Sterilizing immunity: New opportunities for rational TB vaccine design.

    Sher, Alan / Flynn, Joanne L

    The Journal of experimental medicine

    2021  Volume 218, Issue 7

    Abstract: Recent studies have revealed situations of high-level naturally acquired and vaccine-induced immunity against Mycobacterium tuberculosis in animal models along with examples of significantly protective immunization in humans. These discoveries offer ... ...

    Abstract Recent studies have revealed situations of high-level naturally acquired and vaccine-induced immunity against Mycobacterium tuberculosis in animal models along with examples of significantly protective immunization in humans. These discoveries offer immunologists new opportunities to define effector mechanisms that when triggered by appropriately engineered vaccines could end TB's deadly reign.
    MeSH term(s) Animals ; Antigens, Bacterial/immunology ; Humans ; Immunity/immunology ; Immunization/methods ; Mycobacterium tuberculosis/immunology ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tuberculosis Vaccines/immunology
    Chemical Substances Antigens, Bacterial ; Tuberculosis Vaccines
    Language English
    Publishing date 2021-05-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20210454
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  4. Article ; Online: A Third signal from Conditioned DCs dictates microbial effector choice.

    Sher, Alan

    Nature reviews. Immunology

    2016  Volume 16, Issue 12, Page(s) 721

    MeSH term(s) Dendritic Cells ; T-Lymphocytes, Helper-Inducer ; Th1 Cells ; Th2 Cells
    Language English
    Publishing date 2016-11-14
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/nri.2016.126
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  5. Article ; Online: Editorial: The Covid-19 and TB syndemic: differences and similarities.

    Kaufmann, Stefan H E / Sigal, Alex / Sawitzki, Birgit / Sher, Alan

    Frontiers in immunology

    2023  Volume 14, Page(s) 1340231

    MeSH term(s) Humans ; COVID-19 ; Syndemic ; Tuberculosis/epidemiology ; Mycobacterium tuberculosis
    Language English
    Publishing date 2023-11-29
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1340231
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  6. Article ; Online: The Colon as a Major Site of Immunoregulation by CD4

    Sher, Alan / Kelsall, Brian L

    Journal of immunology (Baltimore, Md. : 1950)

    2019  Volume 203, Issue 7, Page(s) 1683–1684

    MeSH term(s) Animals ; Colon/cytology ; Colon/immunology ; Humans ; Interleukin-10/immunology ; Interleukin-4/immunology ; Th1 Cells/cytology ; Th1 Cells/immunology ; Th2 Cells/cytology ; Th2 Cells/immunology
    Chemical Substances IL10 protein, human ; IL4 protein, human ; Interleukin-10 (130068-27-8) ; Interleukin-4 (207137-56-2)
    Language English
    Publishing date 2019-09-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    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.1900960
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  7. Article ; Online: Host-directed immunotherapy of viral and bacterial infections: past, present and future.

    Wallis, Robert S / O'Garra, Anne / Sher, Alan / Wack, Andreas

    Nature reviews. Immunology

    2022  Volume 23, Issue 2, Page(s) 121–133

    Abstract: The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures ...

    Abstract The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures are vaccines but these have been difficult to develop for some of these infectious diseases even after decades of research. The development of drugs and immunotherapies acting directly against the pathogen can be equally challenging, and such pathogen-directed therapeutics have the potential disadvantage of selecting for resistance. An alternative approach is provided by host-directed therapies, which interfere with host cellular processes required for pathogen survival or replication, or target the host immune response to infection (immunotherapies) to either augment immunity or ameliorate immunopathology. Here, we provide a historical perspective of host-directed immunotherapeutic interventions for viral and bacterial infections and then focus on SARS-CoV-2 and Mycobacterium tuberculosis, two major human pathogens of the current era, to indicate the key lessons learned and discuss candidate immunotherapeutic approaches, with a focus on drugs currently in clinical trials.
    MeSH term(s) Humans ; COVID-19/therapy ; SARS-CoV-2 ; Bacterial Infections/therapy ; Immunotherapy ; Communicable Diseases
    Language English
    Publishing date 2022-06-07
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-022-00734-z
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  8. Article ; Online: The Dysbiosis Triggered by First-Line Tuberculosis Antibiotics Fails to Reduce Their Bioavailability.

    Namasivayam, Sivaranjani / Zimmerman, Matthew / Oland, Sandra / Wang, Han / Mittereder, Lara R / Dartois, Véronique / Sher, Alan

    mBio

    2023  Volume 14, Issue 2, Page(s) e0035323

    Abstract: Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the ... ...

    Abstract Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the microbiome might affect the absorption or gut metabolism of the tuberculosis (TB) drugs themselves. To address this issue, we utilized a murine model of antibiotic-induced dysbiosis to assay the bioavailability of rifampicin, moxifloxacin, pyrazinamide, and isoniazid in mouse plasma over a period of 12 h following individual oral administration. We found that 4-week pretreatment with a regimen of isoniazid, rifampicin, and pyrazinamide (HRZ), a drug combination used clinically for ATT, failed to reduce the exposure of any of the four antibiotics assayed. Nevertheless, mice that received a pretreatment cocktail of the broad-spectrum antibiotics vancomycin, ampicllin, neomycin, and metronidazole (VANM), which are known to deplete the intestinal microbiota, displayed a significant decrease in the plasma concentration of rifampicin and moxifloxacin during the assay period, an observation that was validated in germfree animals. In contrast, no major effects were observed when similarly pretreated mice were exposed to pyrazinamide or isoniazid. Thus, the data from this animal model study indicate that the dysbiosis induced by HRZ does not reduce the bioavailability of the drugs themselves. Nevertheless, our observations suggest that more extreme alterations of the microbiota, such as those occurring in patients on broad-spectrum antibiotics, could directly or indirectly affect the exposure of important TB drugs and thereby potentially influencing treatment outcome.
    MeSH term(s) Humans ; Animals ; Mice ; Antitubercular Agents/therapeutic use ; Rifampin/therapeutic use ; Isoniazid/therapeutic use ; Pyrazinamide/therapeutic use ; Biological Availability ; Moxifloxacin/therapeutic use ; Dysbiosis/etiology ; Tuberculosis/microbiology
    Chemical Substances Antitubercular Agents ; Rifampin (VJT6J7R4TR) ; Isoniazid (V83O1VOZ8L) ; Pyrazinamide (2KNI5N06TI) ; Moxifloxacin (U188XYD42P)
    Language English
    Publishing date 2023-03-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.00353-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens.

    Costa, Diego L / Amaral, Eduardo P / Andrade, Bruno B / Sher, Alan

    Antioxidants (Basel, Switzerland)

    2020  Volume 9, Issue 12

    Abstract: Heme oxygenase-1 (HO-1) catalyzes the degradation of heme molecules releasing equimolar amounts of biliverdin, iron and carbon monoxide. Its expression is induced in response to stress signals such as reactive oxygen species and inflammatory mediators ... ...

    Abstract Heme oxygenase-1 (HO-1) catalyzes the degradation of heme molecules releasing equimolar amounts of biliverdin, iron and carbon monoxide. Its expression is induced in response to stress signals such as reactive oxygen species and inflammatory mediators with antioxidant, anti-inflammatory and immunosuppressive consequences for the host. Interestingly, several intracellular pathogens responsible for major human diseases have been shown to be powerful inducers of HO-1 expression in both host cells and in vivo. Studies have shown that this HO-1 response can be either host detrimental by impairing pathogen control or host beneficial by limiting infection induced inflammation and tissue pathology. These properties make HO-1 an attractive target for host-directed therapy (HDT) of the diseases in question, many of which have been difficult to control using conventional antibiotic approaches. Here we review the mechanisms by which HO-1 expression is induced and how the enzyme regulates inflammatory and immune responses during infection with a number of different intracellular bacterial and protozoan pathogens highlighting mechanistic commonalities and differences with the goal of identifying targets for disease intervention.
    Language English
    Publishing date 2020-11-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox9121205
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  10. Article ; Online: Chitosan: An Adjuvant with an Unanticipated STING.

    Riteau, Nicolas / Sher, Alan

    Immunity

    2016  Volume 44, Issue 3, Page(s) 522–524

    Abstract: Adjuvants promote adaptive immunity through the triggering of innate signals that are largely poorly understood. In this issue of Immunity, Lavelle and colleagues describe an unexpected role for the DNA sensing cGAS-STING pathway in the mechanism of ... ...

    Abstract Adjuvants promote adaptive immunity through the triggering of innate signals that are largely poorly understood. In this issue of Immunity, Lavelle and colleagues describe an unexpected role for the DNA sensing cGAS-STING pathway in the mechanism of action of the Th1 cell-promoting polysaccharide adjuvant chitosan.
    MeSH term(s) Adjuvants, Immunologic/administration & dosage ; Animals ; Chitosan/administration & dosage ; Dendritic Cells/physiology ; Female ; Humans ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; Nucleotidyltransferases/metabolism ; Th1 Cells/immunology
    Chemical Substances Adjuvants, Immunologic ; Membrane Proteins ; Chitosan (9012-76-4) ; Nucleotidyltransferases (EC 2.7.7.-)
    Language English
    Publishing date 2016-03-15
    Publishing country United States
    Document type Comment ; Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2016.03.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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