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      Plasmodium falciparum infection dysregulates placental autophagy

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          Abstract

          Plasmodium (P. ) falciparum malaria during pregnancy has been frequently associated with severe consequences such as maternal anemia, abortion, premature birth, and reduced birth weight. Placental damage promotes disruption of the local homeostasis; though, the mechanisms underlying these events are still to be elucidated. Autophagy is a fundamental homeostatic mechanism in the natural course of pregnancy by which cells self-recycle in order to survive in stressful environments. Placentas from non-infected and P. falciparum-infected women during pregnancy were selected from a previous prospective cohort study conducted in the Brazilian Amazon (Acre, Brazil). Newborns from infected women experienced reduced birth weight ( P = 0.0098) and placental immunopathology markers such as monocyte infiltrate ( P < 0.0001) and IL-10 production ( P = 0.0122). The placentas were evaluated for autophagy-related molecules. As a result, we observed reduced mRNA levels of ULK1 ( P = 0.0255), BECN1 ( P = 0.0019), and MAP1LC3B ( P = 0.0086) genes in placentas from P. falciparum-infected, which was more striking in those diagnosed with placental malaria. Despite the protein levels of these genes followed the same pattern, the observed reduction was not statistically significant in placentas from P. falciparum-infected women. Nevertheless, our data suggest that chronic placental immunopathology due to P. falciparum infection leads to autophagy dysregulation, which might impair local homeostasis during malaria in pregnancy that may result in poor pregnancy outcomes.

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          Most cited references39

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          Autophagy and the integrated stress response.

          Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Autophagy in immunity and inflammation

            Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy — the 'autophagy proteins' — orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
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              Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta.

              Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: Resources
                Role: Formal analysisRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 December 2019
                2019
                : 14
                : 12
                : e0226117
                Affiliations
                [1 ] Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
                [2 ] Multidisciplinary Centre, Federal University of Acre, Acre, Brazil
                [3 ] Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
                Instituto Rene Rachou, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors are joint senior authors on this work.

                Author information
                http://orcid.org/0000-0002-1863-1914
                http://orcid.org/0000-0002-7775-6901
                http://orcid.org/0000-0002-1227-3845
                Article
                PONE-D-19-24489
                10.1371/journal.pone.0226117
                6894763
                31805150
                78620327-590d-415b-bb28-dae2d7948ee5
                © 2019 Lima et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 August 2019
                : 18 November 2019
                Page count
                Figures: 2, Tables: 1, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2016/07030-0
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2018/20468-0
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2017/05782-8
                Award Recipient :
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
                Award ID: 141946/2012-1
                Award Recipient :
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
                Award ID: 133890/2016-3
                Award Recipient :
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo (BR)
                Award ID: 2013/16417-8
                Award Recipient :
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo (BR)
                Award ID: 2017/03939-7
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2013/00981-1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2012/04755-3
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2015/06106-0
                Award Recipient :
                This study was mainly funded by grants from the São Paulo Research Foundation (FAPESP) attributed to CRFM (2016/07030-0, 2018/20468-0) and SE (2017/05782-8). RMS and DSC were supported by fellowships from the National Council for Scientific and Technological Development (CNPq) (141946/2012-1 and 133890/2016-3). FAL, AB, OM, JGD, and LAG were supported by FAPESP fellowships (2013/16417-8, 2017/03939-7, 2013/00981-1, 2012/04755-3, and 2015/06106-0, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FAPESP URL: http://www.fapesp.br/en/. CNPq URL: http://memoria.cnpq.br/.
                Categories
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