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      Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice

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          Abstract

          Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.

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          Complex heatmaps reveal patterns and correlations in multidimensional genomic data.

          Parallel heatmaps with carefully designed annotation graphics are powerful for efficient visualization of patterns and relationships among high dimensional genomic data. Here we present the ComplexHeatmap package that provides rich functionalities for customizing heatmaps, arranging multiple parallel heatmaps and including user-defined annotation graphics. We demonstrate the power of ComplexHeatmap to easily reveal patterns and correlations among multiple sources of information with four real-world datasets.
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            circlize Implements and enhances circular visualization in R.

            Circular layout is an efficient way for the visualization of huge amounts of genomic information. Here we present the circlize package, which provides an implementation of circular layout generation in R as well as an enhancement of available software. The flexibility of this package is based on the usage of low-level graphics functions such that self-defined high-level graphics can be easily implemented by users for specific purposes. Together with the seamless connection between the powerful computational and visual environment in R, circlize gives users more convenience and freedom to design figures for better understanding genomic patterns behind multi-dimensional data.
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              PD-1 and its ligands in tolerance and immunity.

              Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.
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                Author and article information

                Contributors
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                04 March 2024
                2024
                : 15
                : 1347318
                Affiliations
                [1] 1 Institute of Science and Technology, Federal University of São Paulo , São Paulo, Brazil
                [2] 2 Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP) , São Paulo, Brazil
                [3] 3 Institute of Mathematics and Statistics (IME), University of Sao Paulo (USP) , Sao Paulo, Brazil
                [4] 4 Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine (USP) , São Paulo, Brazil
                [5] 5 Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP) , São Paulo, Brazil
                [6] 6 Network of Immunity in Infection, Malignancy, Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN) , São Paulo, Brazil
                Author notes

                Edited by: Yong Huang, Northwest A&F University, China

                Reviewed by: James Venturini, Federal University of Mato Grosso do Sul, Brazil

                Lei Chen, Guangdong Ocean University, China

                *Correspondence: Vera Lúcia Garcia Calich, vlcalich@ 123456icb.usp.br
                Article
                10.3389/fimmu.2024.1347318
                10945025
                38500881
                f9c5ea19-ddba-4d1b-830f-e6081fe90b43
                Copyright © 2024 Preite, Borges, Kaminski, Ayupe, Gonçalves, dos Santos, Fonseca, Filgueiras, Salgado, Muxel, Cabral-Marques, da Fonseca, Loures and Calich

                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.

                History
                : 30 November 2023
                : 14 February 2024
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 60, Pages: 17, Words: 8151
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo , doi 10.13039/501100001807;
                Award ID: 2020/08460-4
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by grants and fellowships from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Grants to VC (Nr 2020/08460-4), FL (Nr 2018/14762-3 and Nr 2019/100978), and DMF (Nr 2021/06881-5). PhD, M.Sc, students, and Postdoctoral researchers were also supported by FAPESP fellowships. NP, PhD fellowship Nr 2019/09278-8. BMB, PhD fellowship Nr 2021/09962-6. BS, M.Sc. fellowship Nr 2023/08856-3. VLK, Postdoctoral fellowship Nr 2019/24440-6. MA, PhD fellowship Nr 2019/12691-4. LG, PhD fellowship 2022/10275-6. We also acknowledge FAPESP grants 2018/18886-9 to OC-M and 2023/07806-2 to IF as well as the National Council for Scientific and Technological Development (CNPq) Brazil (grants: 309482/2022-4 to OCM).
                Categories
                Immunology
                Original Research
                Custom metadata
                Microbial Immunology

                Immunology
                pulmonary paracoccidioidomycosis,pd-1 and ctla-4 blockade,protective effect,fungal clearance,reduced dissemination,improved immunity,increased survival,t cell responses

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