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      Staphylococcus aureus Avoids Autophagy Clearance of Bovine Mammary Epithelial Cells by Impairing Lysosomal Function

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          Abstract

          In dairy herds, mastitis caused by Staphylococcus aureus is difficult to completely cure on the account that S. aureus can invade bovine mammary epithelial cells (BMECs) and result in persistent infection in the mammary gland. Recent studies have demonstrated that autophagy can participate in cell homeostasis by eliminating intracellular microorganisms. The aim of the study was to investigate why S. aureus can evade autophagy clearance and survive in BMECs. The intracellular infection model was first constructed; then, the bacteria in autophagosome was detected by transmission electron microscopy. The autophagy flux induced by the S. aureus was also evaluated by immunoblot analysis and fluorescent labeling method for autophagy marker protein LC3. In addition, lysosomal alkalization and degradation ability were assessed using confocal microscopy. Results showed that, after infection, a double-layer membrane structure around the S. aureus was observed in BMECs, indicating that autophagy occurred. The change in autophagy marker protein and fluorescent labeling of autophagosome also confirmed autophagy. However, as time prolonged, the autophagy flux was markedly inhibited, leading to obvious autophagosome accumulation. At the same time, the lysosomal alkalization and degradation ability of BMECs were impaired. Collectively, these results indicated that S. aureus could escape autophagic degradation by inhibiting autophagy flux and damaging lysosomal function after invading BMECs.

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          Most cited references30

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          Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death.

          Staphylococcus aureus is a common bacterial etiology of serious infectious diseases. S. aureus can invade various types of non-professional phagocytes to produce host cell death. We show here that shortly after invasion of HeLa cells S. aureus transit to autophagosomes was characterized by double membranes and co-localization with LC3. S. aureus were not able to replicate and produce cell death in autophagy-deficient atg5-/- mouse embryonic fibroblasts. S. aureus-containing autophagosomes do not acidify nor do they acquire lysosome-associated membrane protein-2, indicating that S. aureus inhibits autophagosome maturation and fusion with lysosomes. Eventually, S. aureus escape from autophagosomes into the cytoplasm, which results in caspase-independent host cell death. S. aureus strains deficient for agr, a global regulator of S. aureus virulence, were not targeted by autophagy and did not produce host-cell death. Autophagy induction by rapamycin restored both replication and cytotoxicity of agr-deficient S. aureus strains, indicating that an agr-regulated factor(s) is required for autophagy-mediated cytotoxicity. The results of this study suggest that rapid induction of autophagy is essential for S. aureus replication, escape into the cytoplasm, and host cell killing.
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            Evaluation of acridine orange, LysoTracker Red, and quinacrine as fluorescent probes for long-term tracking of acidic vesicles.

            Acidic vesicles can be imaged and tracked in live cells after staining with several low molecular weight fluorescent probes, or with fluorescently labeled proteins. Three fluorescent dyes, acridine orange, LysoTracker Red DND-99, and quinacrine, were evaluated as acidic vesicle tracers for confocal fluorescence imaging and quantitative analysis. The stability of fluorescent signals, achievable image contrast, and phototoxicity were taken into consideration. The three tested tracers exhibit different advantages and pose different problems in imaging experiments. Acridine orange makes it possible to distinguish acidic vesicles with different internal pH but is fairly phototoxic and can cause spectacular bursts of the dye-loaded vesicles. LysoTracker Red is less phototoxic but its rapid photobleaching limits the range of useful applications considerably. We demonstrate that quinacrine is most suitable for long-term imaging when a high number of frames is required. This capacity made it possible to trace acidic vesicles for several hours, during a process of drug-induced apoptosis. An ability to record the behavior of acidic vesicles over such long periods opens a possibility to study processes like autophagy or long-term effects of drugs on endocytosis and exocytosis.
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              Inhibition of the autophagic flux by salinomycin in breast cancer stem-like/progenitor cells interferes with their maintenance.

              Breast cancer tissue contains a small population of cells that have the ability to self-renew; these cells are known as cancer stem-like cells (CSCs). We have recently shown that autophagy is essential for the tumorigenicity of these CSCs. Salinomycin (Sal), a K (+) /H (+) ionophore, has recently been shown to be at least 100 times more effective than paclitaxel in reducing the proportion of breast CSCs. However, its mechanisms of action are still unclear. We show here that Sal blocked both autophagy flux and lysosomal proteolytic activity in both CSCs and non-CSCs derived from breast cancer cells. GFP-LC3 staining combined with fluorescent dextran uptake and LysoTracker-Red staining showed that autophagosome/lysosome fusion was not altered by Sal treatment. Acridine orange staining provided evidence that lysosomes display the characteristics of acidic compartments in Sal-treated cells. However, tandem mCherry-GFP-LC3 assay indicated that the degradation of mCherry-GFP-LC3 is blocked by Sal. Furthermore, the protein degradation activity of lysosomes was inhibited, as demonstrated by the rate of long-lived protein degradation, DQ-BSA assay and measurement of cathepsin activity. Our data indicated that Sal has a relatively greater suppressant effect on autophagic flux in the ALDH (+) population in HMLER cells than in the ALDH (-) population; moreover, this differential effect on autophagic flux correlated with an increase in apoptosis in the ALDH (+) population. ATG7 depletion accelerated the proapoptotic capacity of Sal in the ALDH (+) population. Our findings provide new insights into how the autophagy-lysosomal pathway contributes to the ability of Sal to target CSCs in vitro.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                05 May 2020
                2020
                : 11
                : 746
                Affiliations
                [1] 1College of Veterinary Medicine, Shandong Agricultural University , Tai’an, China
                [2] 2China Animal Health and Epidemiology Center , Qingdao, China
                [3] 3Research Center for Animal Disease Control Engineering, Shandong Agricultural University , Tai’an, China
                Author notes

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

                Reviewed by: Marisa Mariel Fernandez, Institute of Studies on Humoral Immunity (IDEHU), Argentina; Emile Santos Barrias, National Institute of Metrology, Quality and Technology, Brazil

                *Correspondence: Jianzhu Liu, liujz@ 123456sdau.edu.cn

                These authors have contributed equally to this work

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

                Article
                10.3389/fimmu.2020.00746
                7214833
                32431700
                45581981-00e5-42eb-b454-77d60cb400d4
                Copyright © 2020 Geng, Wang, Yu, Wang, Zhu, Zhang, Liu and Liu.

                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
                : 18 October 2019
                : 01 April 2020
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 38, Pages: 9, Words: 0
                Categories
                Immunology
                Original Research

                Immunology
                staphylococcus aureus,bovine mammary epithelial cells,intracellular infection,autophagy,lysosomes

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