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1.
Cell ; 184(15): 3915-3935.e21, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1283262

ABSTRACT

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.


Subject(s)
Epigenomics , Immunity/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Single-Cell Analysis , Transcription, Genetic , Vaccination , Adolescent , Adult , Anti-Bacterial Agents/pharmacology , Antigens, CD34/metabolism , Antiviral Agents/pharmacology , Cellular Reprogramming , Chromatin/metabolism , Cytokines/biosynthesis , Drug Combinations , Female , Gene Expression Regulation , Histones/metabolism , Humans , Immunity, Innate/genetics , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/immunology , Interferon Type I/metabolism , Male , Myeloid Cells/metabolism , Polysorbates/pharmacology , Squalene/pharmacology , Toll-Like Receptors/metabolism , Transcription Factor AP-1/metabolism , Transcriptome/genetics , Young Adult , alpha-Tocopherol/pharmacology
2.
J Allergy Clin Immunol ; 148(3): 843-857.e6, 2021 09.
Article in English | MEDLINE | ID: covidwho-1213300

ABSTRACT

BACKGROUND: Prenatal exposure to infections can modify immune development. These environmental disturbances during early life potentially alter the incidence of inflammatory disorders as well as priming of immune responses. Infection with the helminth Schistosoma mansoni is widely studied for its ability to alter immune responsiveness and is associated with variations in coinfection, allergy, and vaccine efficacy in endemic populations. OBJECTIVE: Exposure to maternal schistosomiasis during early life, even without transmission of infection, can result in priming effects on offspring immune responses to bystander antigenic challenges as related to allergic responsiveness and vaccination, with this article seeking to further clarify the effects and underlying immunologic imprinting. METHODS: Here, we have combined a model of chronic maternal schistosomiasis infection with a thorough analysis of subsequent offspring immune responses to allergy and vaccination models, including viral challenge and steady-state changes to immune cell compartments. RESULTS: We have demonstrated that maternal schistosomiasis alters CD4+ responses during allergic sensitization and challenge in a skewed IL-4/B-cell-dominant response to antigenic challenge associated with limited inflammatory response. Beyond that, we have uncovered previously unidentified alterations to CD8+ T-cell responses during immunization that are dependent on vaccine formulation and have functional impact on the efficacy of vaccination against viral infection in a murine hepatitis B virus model. CONCLUSION: In addition to steady-state modifications to CD4+ T-cell polarization and B-cell priming, we have traced these modified CD8+ responses to an altered dendritic cell phenotype sustained into adulthood, providing evidence for complex priming effects imparted by infection via fetomaternal cross talk.


Subject(s)
Prenatal Exposure Delayed Effects/immunology , Respiratory Hypersensitivity/immunology , Schistosomiasis/immunology , Allergens/immunology , Animals , B-Lymphocytes/immunology , Cells, Cultured , Dendritic Cells/immunology , Female , Fetus/immunology , Gene Expression Profiling , Immunization , Lung/immunology , Lymph Nodes/immunology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Ovalbumin/immunology , Pregnancy , Respiratory Hypersensitivity/genetics , Schistosoma mansoni , Spleen/immunology , T-Lymphocytes/immunology
3.
Hum Vaccin Immunother ; 17(6): 1604-1606, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1027687

ABSTRACT

The innate immune system, through pattern recognition receptors, intercepts any kind of pathogen and reacts through chemotactic, phagocyting, cytokines-secreting and cell-killing mechanisms in a very quick and effective way. Meanwhile, the adaptive immunity arm, through dendritic and T and B cells memory activation, is alerted and starts, more slowly, to produce antibodies, seen thanks to the progress of immunological investigations in comparative vertebrates, invertebrates, and vegetal models.However, it has been stated that the innate immune system also displays adaptive potential in terms of reinfection resistance through immune memory, in addition to the modulation of responses against repeated low doses of lipopolysaccharides (Lps) or cross-immunization, starting from one pathogenic species and extending to others.


Subject(s)
Biological Evolution , Immunity, Innate , Immunologic Memory , Adaptive Immunity , Animals , B-Lymphocytes/immunology , T-Lymphocytes/immunology
4.
Cell Microbiol ; 22(12): e13261, 2020 12.
Article in English | MEDLINE | ID: covidwho-755319

ABSTRACT

Infectious diseases are a leading cause of death worldwide with over 8 million fatalities accounted for in 2016. Solicitation of host immune defenses by vaccination is the treatment of choice to prevent these infections. It has long been thought that vaccine immunity was solely mediated by the adaptive immune system. However, over the past decade, numerous studies have shown that innate immune cells can also retain memory of these encounters. This process, called innate immune memory, is mediated by metabolic and epigenetic changes that make cells either hyperresponsive (trained immunity) or hyporesponsive (tolerance) to subsequent challenges. In this review, we discuss the concepts of trained immunity and tolerance in the context of host-pathogen interactions.


Subject(s)
Adaptive Immunity/immunology , Host-Pathogen Interactions/immunology , Immune Tolerance , Immunity, Innate/immunology , Immunologic Memory , Epigenesis, Genetic/immunology , Humans , Vaccines/administration & dosage , Vaccines/immunology
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