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      Heterogeneity in pneumolysin expression governs the fate of Streptococcus pneumoniae during blood-brain barrier trafficking

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Outcome of host-pathogen encounter is determined by the complex interplay between protective bacterial and host defense strategies. This complexity further amplifies with the existence of cell-to-cell phenotypic heterogeneity in pathogens which remains largely unexplored. In this study, we illustrated that heterogeneous expression of pneumolysin (Ply), a pore-forming toxin of the meningeal pathogen, S. pneumoniae (SPN) gives rise to stochastically different bacterial subpopulations with variable fate during passage across blood-brain barrier (BBB). We demonstrate that Ply mediated damage to pneumococcus containing vacuolar (PCV) membrane leads to recruitment of cytosolic “eat-me” signals, galectin-8 and ubiquitin, targeting SPN for autophagic clearance. However, a majority of high Ply producing subset extensively damages autophagosomes leading to pneumococcal escape into cytosol and efficient clearance by host ubiquitination machinery. Interestingly, a low Ply producing subset halts autophagosomal maturation and evades all intracellular defense mechanisms, promoting its prolonged survival and successful transcytosis across BBB, both in vitro and in vivo. Ply therefore acts as both, sword and shield implying that its smart regulation ensures optimal disease manifestation. Our elucidation of heterogeneity in Ply expression leading to disparate infection outcomes attempts to resolve the dubious role of Ply in pneumococcal pathogenesis.

          Author summary

          Streptococcus pneumoniae, the Gram-positive diplococci, is the primary etiological agent of bacterial meningitis. In order to cause central nervous system (CNS) infections, SPN has to breach the blood-brain barrier, however, the pneumococcal determinants involved in this process remain unidentified. Here, we demonstrate that pneumolysin, a pore forming toxin secreted by SPN, plays a complex role in governing the fate of the pathogen while trafficking through BBB. Though presumed to be an important virulence attribute, the role of Ply in SPN pathogenesis, particularly in development of meningitis remained debatable. By revealing heterogeneity in Ply expression within isogenic SPN population, our findings attempt to resolve the uncertain role of Ply in SPN pathogenesis. We illustrate that heterogeneity in Ply expression gives rise to stochastically different pneumococcal subpopulations during BBB trafficking. This arises as a consequence of differential interactions of SPN with host microbicidal defense pathways like autophagy and ubiquitination machinery. Among the stochastic SPN population, a low Ply producing SPN subset not only shows improved persistence, but is also capable of successful transcytosis across the BBB resulting in CNS pathogenesis. Overall, our findings suggest that tight spatio-temporal regulation of Ply expression is key to SPN subsistence and dissemination within the host.

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          Most cited references 48

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          Autophagy defends cells against invading group A Streptococcus.

          We found that the autophagic machinery could effectively eliminate pathogenic group A Streptococcus (GAS) within nonphagocytic cells. After escaping from endosomes into the cytoplasm, GAS became enveloped by autophagosome-like compartments and were killed upon fusion of these compartments with lysosomes. In autophagy-deficient Atg5-/- cells, GAS survived, multiplied, and were released from the cells. Thus, the autophagic machinery can act as an innate defense system against invading pathogens.
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            Escape of intracellular Shigella from autophagy.

            The degradation of undesirable cellular components or organelles, including invading microbes, by autophagy is crucial for cell survival. Here, Shigella, an invasive bacteria, was found to be able to escape autophagy by secreting IcsB by means of the type III secretion system. Mutant bacteria lacking IcsB were trapped by autophagy during multiplication within the host cells. IcsB did not directly inhibit autophagy. Rather, Shigella VirG, a protein required for intracellular actin-based motility, induced autophagy by binding to the autophagy protein, Atg5. In nonmutant Shigella, this binding is competitively inhibited by IcsB binding to VirG.
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              Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation.

              Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M. tuberculosis infection of Atg5(fl/fl) LysM-Cre(+) mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophil infiltration and IL-17 response with increased IL-1α levels. Macrophages from uninfected Atg5(fl/fl) LysM-Cre(+) mice displayed a cell-autonomous IL-1α hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ResourcesRole: Validation
                Role: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                16 July 2018
                July 2018
                : 14
                : 7
                Affiliations
                [1 ] Bacterial Pathogenesis Lab, Dept. of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, INDIA
                [2 ] Dept. of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, INDIA
                [3 ] Centre for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru, INDIA
                [4 ] National Centre for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health (ICMR), J. M. Street, Parel, Mumbai, INDIA
                [5 ] Division of Pediatric Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America
                St. Jude Children's Research Hospital, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-18-00347
                10.1371/journal.ppat.1007168
                6062133
                30011336
                © 2018 Surve 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.

                Page count
                Figures: 10, Tables: 0, Pages: 29
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001412, Council of Scientific and Industrial Research;
                Award ID: 37(1626)/14/EMR-II
                Award Recipient :
                Financial assistance from Council of Scientific and Industrial Research (CSIR), Govt. of India [37(1626)/14/EMR-II] and Science and Engineering Research Board (SERB), Govt. of India (EMR/2016/005909) to AB is acknowledged. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MVS and SB acknowledge fellowship from University Grant Commission, Govt. of India, and AA acknowledges the same from Council of Scientific and Industrial Research (CSIR), Govt. of India.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Analysis of Variance
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Analysis of Variance
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Intracellular Pathogens
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Autophagic Cell Death
                Biology and Life Sciences
                Cell Biology
                Cytosol
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Endothelium
                Biology and Life Sciences
                Genetics
                Mutation
                Mutant Strains
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-07-26
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology

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