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

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

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
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Article ; Online: Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses.

Hilligan, Kerry L / Ronchese, Franca

Cellular & molecular immunology

2020 Volume 17, Issue 6, Page(s) 587–599

Abstract: Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and co-stimulatory molecules for naive T cell activation and expansion, dendritic cells are ... ...

Abstract	Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and co-stimulatory molecules for naive T cell activation and expansion, dendritic cells are thought to also provide signals for the differentiation of CD4+ T cells into effector T cell populations. The mechanisms by which dendritic cells are able to adapt and respond to the great variety of infectious stimuli they are confronted with, and prime an appropriate CD4+ T cell response, are only partly understood. It is known that in the steady-state dendritic cells are highly heterogenous both in phenotype and transcriptional profile, and that this variability is dependent on developmental lineage, maturation stage, and the tissue environment in which dendritic cells are located. Exposure to infectious agents interfaces with this pre-existing heterogeneity by providing ligands for pattern-recognition and toll-like receptors that are variably expressed on different dendritic cell subsets, and elicit production of cytokines and chemokines to support innate cell activation and drive T cell differentiation. Here we review current information on dendritic cell biology, their heterogeneity, and the properties of different dendritic cell subsets. We then consider the signals required for the development of different types of Th immune responses, and the cellular and molecular evidence implicating different subsets of dendritic cells in providing such signals. We outline how dendritic cell subsets tailor their response according to the infectious agent, and how such transcriptional plasticity enables them to drive different types of immune responses.
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Cell Differentiation/immunology ; Dendritic Cells/immunology ; Humans ; Models, Biological ; T-Lymphocytes, Helper-Inducer/immunology ; Transcription, Genetic
Language	English
Publishing date	2020-05-20
Publishing country	China
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2435097-7
ISSN	2042-0226 ; 1672-7681
ISSN (online)	2042-0226
ISSN	1672-7681
DOI	10.1038/s41423-020-0465-0
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Article ; Online: Dendritic cells and the skin environment.

Ronchese, Franca / Hilligan, Kerry L / Mayer, Johannes U

Current opinion in immunology

2020 Volume 64, Page(s) 56–62

Abstract: The skin is inhabited by several immune cell populations that serve as a first line of defence against pathogen invasion. Amongst these populations are dendritic cells, which play an essential sentinel function by taking up antigen or infectious agents ... ...

Abstract	The skin is inhabited by several immune cell populations that serve as a first line of defence against pathogen invasion. Amongst these populations are dendritic cells, which play an essential sentinel function by taking up antigen or infectious agents and transporting them to the lymph node for T cell recognition and the priming of immune responses. In this review, we briefly summarise recent advances showing how skin dendritic cells are connected to a network of epithelial and stromal cells, which provide structural support, growth factors, spatial cues, contact with the external environment and the skin microbiome, and favour interactions with other immune cells. We propose that this network creates a unique skin environment that may condition dendritic cell phenotype and function.
MeSH term(s)	Dendritic Cells ; Humans ; Langerhans Cells ; Lymph Nodes ; Microbiota ; Skin
Language	English
Publishing date	2020-05-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2020.03.006
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Article ; Online: Co-infection of mice with SARS-CoV-2 and

Baker, Paul J / Amaral, Eduardo P / Castro, Ehydel / Bohrer, Andrea C / Torres-Juárez, Flor / Jordan, Cassandra M / Nelson, Christine E / Barber, Daniel L / Johnson, Reed F / Hilligan, Kerry L / Mayer-Barber, Katrin D

Frontiers in immunology

2023 Volume 14, Page(s) 1240419

Abstract: Viral co-infections have been implicated in worsening tuberculosis (TB) and during the COVID-19 pandemic, the global rate of TB-related deaths has increased for the first time in over a decade. We and others have previously shown that a resolved prior or ...

Abstract	Viral co-infections have been implicated in worsening tuberculosis (TB) and during the COVID-19 pandemic, the global rate of TB-related deaths has increased for the first time in over a decade. We and others have previously shown that a resolved prior or concurrent influenza A virus infection in
MeSH term(s)	Mice ; Animals ; Humans ; Mycobacterium tuberculosis ; SARS-CoV-2 ; Coinfection ; Pandemics ; COVID-19 ; Mice, Transgenic ; Interferon Type I ; Mice, Inbred C57BL
Chemical Substances	K-18 conjugate ; Interferon Type I
Language	English
Publishing date	2023-09-01
Publishing country	Switzerland
Document type	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.2023.1240419
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Article: The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication.

Baker, Paul J / Bohrer, Andrea C / Castro, Ehydel / Amaral, Eduardo P / Snow-Smith, Maryonne / Torres-Juárez, Flor / Gould, Sydnee T / Queiroz, Artur T L / Fukutani, Eduardo R / Jordan, Cassandra M / Khillan, Jaspal S / Cho, Kyoungin / Barber, Daniel L / Andrade, Bruno B / Johnson, Reed F / Hilligan, Kerry L / Mayer-Barber, Katrin D

bioRxiv : the preprint server for biology

2024

Abstract: SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of ... ...

Abstract	SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. We demonstrate here that immune events in the mouse lung closely preceding SARS-CoV-2 infection significantly impact viral control and we identify key innate immune pathways required to limit viral replication. A diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections with
Language	English
Publishing date	2024-03-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.27.586885
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Article: Helminth exposure protects against murine SARS-CoV-2 infection through macrophage dependent T cell activation.

Hilligan, Kerry L / Oyesola, Oyebola O / Namasivayam, Sivaranjani / Howard, Nina / Clancy, Chad S / Oland, Sandra D / Garza, Nicole L / Lafont, Bernard A P / Johnson, Reed F / Mayer-Barber, Katrin D / Sher, Alan / Loke, P'ng

bioRxiv : the preprint server for biology

2022

Language	English
Publishing date	2022-11-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.11.09.515832
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Article ; Online: Exposure to lung-migrating helminth protects against murine SARS-CoV-2 infection through macrophage-dependent T cell activation.

Oyesola, Oyebola O / Hilligan, Kerry L / Namasivayam, Sivaranjani / Howard, Nina / Clancy, Chad S / Zhao, Mingming / Oland, Sandra D / Kiwanuka, Kasalina N / Garza, Nicole L / Lafont, Bernard A P / Johnson, Reed F / Mayer-Barber, Katrin D / Sher, Alan / Loke, P'ng

Science immunology

2023 Volume 8, Issue 86, Page(s) eadf8161

Abstract: Helminth endemic regions report lower COVID-19 morbidity and mortality. Here, we show that lung remodeling from a prior infection with a lung-migrating helminth, ...

Abstract	Helminth endemic regions report lower COVID-19 morbidity and mortality. Here, we show that lung remodeling from a prior infection with a lung-migrating helminth,
MeSH term(s)	Mice ; Humans ; Animals ; CD8-Positive T-Lymphocytes ; COVID-19/metabolism ; SARS-CoV-2 ; Macrophages ; Lung ; Mice, Transgenic
Language	English
Publishing date	2023-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adf8161
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Article: Evaluation of endogenous and therapeutic 25-hydroxycholesterols in murine models of pulmonary SARS-CoV-2 infection.

Fessler, Michael B / Madenspacher, Jennifer / Baker, Paul J / Hilligan, Kerry L / Castro, Ehydel / Meacham, Julie / Chen, Shih-Heng / Johnson, Reed F / Martin, Negin P / Tucker, C J / Mahapatra, Debabrata / Cesta, Mark / Mayer-Barber, Katrin D

bioRxiv : the preprint server for biology

2022

Abstract: Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-hydroxycholesterol (25HC), a product of activity of cholesterol-25-hydroxylase (CH25H) upon cholesterol, has recently been shown to be broadly antiviral, suggesting ... ...

Abstract	Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-hydroxycholesterol (25HC), a product of activity of cholesterol-25-hydroxylase (CH25H) upon cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against SARS-CoV-2. However, 25HC can also amplify inflammation and tissue injury and be converted by CYP7B1 to 7α,25HC, a lipid with chemoattractant activity via the G protein-coupled receptor, EBI2/GPR183. Here, using
Language	English
Publishing date	2022-09-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.09.12.507671
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Article ; Online: Endogenous and Therapeutic 25-Hydroxycholesterols May Worsen Early SARS-CoV-2 Pathogenesis in Mice.

Fessler, Michael B / Madenspacher, Jennifer H / Baker, Paul J / Hilligan, Kerry L / Bohrer, Andrea C / Castro, Ehydel / Meacham, Julie / Chen, Shih-Heng / Johnson, Reed F / McDonald, Jeffrey G / Martin, Negin P / Tucker, Charles J / Mahapatra, Debabrata / Cesta, Mark / Mayer-Barber, Katrin D

American journal of respiratory cell and molecular biology

2023 Volume 69, Issue 6, Page(s) 638–648

Abstract: Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase (CH25H) on cholesterol, has recently been shown to be broadly antiviral, suggesting ... ...

Abstract	Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase (CH25H) on cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, 25HC can also amplify inflammation and be converted by CYP7B1 (cytochrome P450 family 7 subfamily B member 1) to 7α,25-dihydroxycholesterol, a lipid with chemoattractant activity, via the G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2)/GPR183 (G protein-coupled receptor 183). Here, using
MeSH term(s)	Humans ; Animals ; Mice ; SARS-CoV-2 ; Epstein-Barr Virus Infections ; COVID-19 ; Herpesvirus 4, Human ; Hydroxycholesterols/pharmacology ; Cholesterol ; Receptors, G-Protein-Coupled ; Antiviral Agents/pharmacology ; Cytokines ; Weight Loss
Chemical Substances	25-hydroxycholesterol (767JTD2N31) ; NIBR189 ; Hydroxycholesterols ; Cholesterol (97C5T2UQ7J) ; Receptors, G-Protein-Coupled ; Antiviral Agents ; Cytokines ; Gpr183 protein, mouse
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2023-0007OC
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Zs.A 2851: Show issues

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Article ; Online: Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2.

Hilligan, Kerry L / Namasivayam, Sivaranjani / Clancy, Chad S / Baker, Paul J / Old, Samuel I / Peluf, Victoria / Amaral, Eduardo P / Oland, Sandra D / O'Mard, Danielle / Laux, Julie / Cohen, Melanie / Garza, Nicole L / Lafont, Bernard A P / Johnson, Reed F / Feng, Carl G / Jankovic, Dragana / Lamiable, Olivier / Mayer-Barber, Katrin D / Sher, Alan

Nature communications

2023 Volume 14, Issue 1, Page(s) 8229

Abstract: Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved ... ...

Abstract	Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role of Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 in mice yet drives low levels of type-1 IFNs but robust IFNγ. Here we examine the role of ongoing IFNγ responses to pre-established bacterial infection on SARS-CoV-2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads, an outcome dependent on IFNγ receptor expression by non-hematopoietic cells. Importantly, we show that BCG infection prompts pulmonary epithelial cells to upregulate IFN-stimulated genes with reported anti-viral activity in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirm the anti-viral properties of IFNγ by demonstrating that the recombinant cytokine itself provides strong protection against SARS-CoV-2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SARS-CoV-2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SARS-CoV-2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.
MeSH term(s)	Animals ; Mice ; SARS-CoV-2 ; Interferon-gamma ; COVID-19/prevention & control ; Lung ; Interferon Type I/pharmacology
Chemical Substances	Interferon-gamma (82115-62-6) ; Interferon Type I
Language	English
Publishing date	2023-12-12
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/s41467-023-43447-0
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