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      BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design


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          The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as “trained immunity.” Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a “trained” state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

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          Understanding the tumor immune microenvironment (TIME) for effective therapy

          The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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            Chromatin modifications and their function.

            The surface of nucleosomes is studded with a multiplicity of modifications. At least eight different classes have been characterized to date and many different sites have been identified for each class. Operationally, modifications function either by disrupting chromatin contacts or by affecting the recruitment of nonhistone proteins to chromatin. Their presence on histones can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA. In this way, histone modifications have the potential to influence many fundamental biological processes, some of which may be epigenetically inherited.
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              Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.

              Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. Copyright © 2014, American Association for the Advancement of Science.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                29 November 2019
                : 10
                : 2806
                [1] 1Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile
                [2] 2Departamento de Biotecnología, Facultad de Ciencias del Mar y Recursos Biológicos, Universidad de Antofagasta , Antofagasta, Chile
                [3] 3Sección de Biotecnología, Instituto de Salud Pública de Chile , Santiago, Chile
                [4] 4Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia , Santiago, Chile
                [5] 5Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello , Santiago, Chile
                [6] 6Departamento de Endocrinología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
                Author notes

                Edited by: Babita Agrawal, University of Alberta, Canada

                Reviewed by: Mihai Netea, Radboud University Nijmegen, Netherlands; Estrella Mariel Levy, National Council for Scientific and Technical Research (CONICET), Argentina

                *Correspondence: Alexis M. Kalergis akalergis@ 123456bio.puc.cl

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Copyright © 2019 Covián, Fernández-Fierro, Retamal-Díaz, Díaz, Vasquez, Lay, Riedel, González, Bueno and Kalergis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 10 October 2019
                : 15 November 2019
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 145, Pages: 14, Words: 11092
                Funded by: Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica 10.13039/501100010751
                Award ID: 1170694
                Award ID: 1190830
                Award ID: 1190864
                Funded by: Comisión Nacional de Investigación Científica y Tecnológica 10.13039/501100002848

                bcg,innate immunity,trained immunity,heterologous protection,vaccine
                bcg, innate immunity, trained immunity, heterologous protection, vaccine


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