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      Cyclophosphamide Treatment Mimics Sub-Lethal Infections With Encephalitozoon intestinalis in Immunocompromised Individuals

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          Abstract

          Microsporidia, including Encephalitozoon intestinalis, are emerging pathogens which cause opportunistic infections in immunocompromised patients, such as those with AIDS, cancer, the elderly and people on immunosuppressive drugs. Intestinal mucosa (IM) is crucial for developing an efficient adaptive immune response against pathogenic micro-organisms, thereby preventing their colonization and subsequent infection. As immunosuppressive drugs affect the intestinal immune response is little known. In the present study, we investigated the immune response to E. intestinalis infection in the IM and gut-associated lymphoid tissue (GALT) in cyclophosphamide (Cy) immunosuppressed mice, to mimic an immunocompromised condition. Histopathology revealed lymphoplasmacytic enteritis at 7 and 14 days-post-infection (dpi) in all infected groups, however, inflammation diminished at 21 and 28 dpi. Cy treatment also led to a higher number of E. intestinalis spores and lesions, which reduced at 28 dpi. In addition, flow cytometry analysis demonstrated CD4 + and CD8 + T cells to be predominant immune cells, with up-regulation in both Th1 and Th2 cytokines at 7 and 14 dpi, as demonstrated by histopathology. In conclusion, Cy treatment reduced GALT (Peyer’s plaques and mesenteric lymph nodes) and peritoneum populations but increased the T-cell population in the intestinal mucosa and the production of pro-and anti-inflammatory cytokines, which were able to eliminate this opportunistic fungus and reduced the E. intestinalis infection.

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          Most cited references46

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          The Intestinal Epithelium: Central Coordinator of Mucosal Immunity

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            Bacterial invasion: the paradigms of enteroinvasive pathogens.

            Invasive bacteria actively induce their own uptake by phagocytosis in normally nonphagocytic cells and then either establish a protected niche within which they survive and replicate, or disseminate from cell to cell by means of an actin-based motility process. The mechanisms underlying bacterial entry, phagosome maturation, and dissemination reveal common strategies as well as unique tactics evolved by individual species to establish infection.
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              Immunomodulatory effects of cyclophosphamide and implementations for vaccine design.

              Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/810058/overview
                URI : http://loop.frontiersin.org/people/810911/overview
                URI : http://loop.frontiersin.org/people/98918/overview
                URI : http://loop.frontiersin.org/people/810206/overview
                URI : http://loop.frontiersin.org/people/739759/overview
                URI : http://loop.frontiersin.org/people/810289/overview
                URI : http://loop.frontiersin.org/people/133261/overview
                URI : http://loop.frontiersin.org/people/108876/overview
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                25 September 2019
                2019
                : 10
                : 2205
                Affiliations
                [1] 1Programa de Pós-Graduação em Patologia Ambiental e Experimental, Universidade Paulista (UNIP) , São Paulo, Brazil
                [2] 2Departamento de Fisiopatologia, Instituto Butantan , São Paulo, Brazil
                Author notes

                Edited by: Wanderley De Souza, Federal University of Rio de Janeiro, Brazil

                Reviewed by: Louis Weiss, Albert Einstein College of Medicine, United States; Andreas Kupz, James Cook University, Australia

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2019.02205
                6773878
                33872958-bfe0-494f-a489-6b55001ffaa6
                Copyright © 2019 Moura, Alvares-Saraiva, Pérez, Xavier, Spadacci-Morena, Moysés, Rocha and Lallo.

                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
                : 15 July 2019
                : 09 September 2019
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 55, Pages: 13, Words: 0
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                encephalitozoon intestinalis,microsporidia,mucosal immunity,intestinal inflammation,cyclophosphamide

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