1. Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells
- Author
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Areejit Samal, Sara Zaldívar-López, Claire Maudet, Ana Eulalio, Miguel Mano, Juan J. Garrido, Carmen Aguilar, Susana P. G. Costa, R.P. Vivek-Ananth, [Aguilar, Carmen] Univ Wurzburg, Inst Mol Infect Biol IMIB, Host RNA Metab Grp, Wurzburg, Germany, [Maudet, Claire] Univ Wurzburg, Inst Mol Infect Biol IMIB, Host RNA Metab Grp, Wurzburg, Germany, [Eulalio, Ana] Univ Wurzburg, Inst Mol Infect Biol IMIB, Host RNA Metab Grp, Wurzburg, Germany, [Costa, Susana] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, RNA & Infect Lab, Coimbra, Portugal, [Eulalio, Ana] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, RNA & Infect Lab, Coimbra, Portugal, [Costa, Susana] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, Funct Genom & RNA Based Therapeut Lab, Coimbra, Portugal, [Mano, Miguel] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, Funct Genom & RNA Based Therapeut Lab, Coimbra, Portugal, [Costa, Susana] Univ Coimbra, Inst Interdisciplinary Res IIIUC, PhD Programme Expt Biol & Biomed PDBEB, Coimbra, Portugal, [Vivek-Ananth, R. P.] Homi Bhabha Natl Inst HBNI, Inst Math Sci IMSc, Chennai, Tamil Nadu, India, [Samal, Areejit] Homi Bhabha Natl Inst HBNI, Inst Math Sci IMSc, Chennai, Tamil Nadu, India, [Zaldivar-Lopez, Sara] Univ Cordoba, Fac Vet Sci, Dept Genet, Anim Breeding & Genom Grp, Cordoba, Spain, [Garrido, Juan J.] Univ Cordoba, Fac Vet Sci, Dept Genet, Anim Breeding & Genom Grp, Cordoba, Spain, [Zaldivar-Lopez, Sara] Maimonides Biomed Res Inst Cordoba IMIBIC, Immunogen & Mol Pathogenesis GA14 Grp, Cordoba, Spain, [Garrido, Juan J.] Maimonides Biomed Res Inst Cordoba IMIBIC, Immunogen & Mol Pathogenesis GA14 Grp, Cordoba, Spain, [Mano, Miguel] Univ Coimbra, Dept Life Sci, Coimbra, Portugal, [Eulalio, Ana] Univ Coimbra, Dept Life Sci, Coimbra, Portugal, [Maudet, Claire] Inst Pasteur, Biol Infect Unit, Paris, France, Bayerischen Gleichstellungsforderung (BGF) through the SCIENTIA Program, Portuguese Foundation for Science and Technology, Bavarian Ministry of Sciences, Research and the Arts, DFG, ERDF - European Regional Development Fund through COMPETE 2020, FCT Investigator Programme, Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India, Ramanujan fellowship, Spanish Ministry of Economy and Competitiveness, [Aguilar,C, Maudet,C, Eulalio,A] Host RNA Metabolism Group, Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg, Germany. [Costa,S, Eulalio,A] RNA & Infection Laboratory, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal. [Costa,S, Mano,M] Functional Genomics and RNA-based Therapeutics Laboratory, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal. [Costa,S] PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. [Vivek-Ananth,RP, Samal,A] The Institute of Mathematical Sciences (IMSc), Homi Bhabha National Institute (HBNI), Chennai, India. [Zaldívar-López,S, Garrido,JJ] Animal Breeding and Genomics Group, Department of Genetics, Faculty of Veterinary Science, University of Córdoba, Córdoba, Spain. [Zaldívar-López,S, Garrido,JJ] Immunogenomics and Molecular Pathogenesis GA14 Group, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. [Mano,M, Eulalio,A] Department of Life Sciences, University of Coimbra, Coimbra, Portugal., and This work was supported by grants from the Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network (BioSysNet), DFG project BR 4837/1- 1, ERDF - European Regional Development Fund through COMPETE 2020 and the Portuguese Foundation for Science and Technology (POCI-01-0145-FEDER-007440, UIDB/ 04539/2020, and FCT Investigator Programme IF/01105/2015) to A.E., and the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India, Ramanujan fellowship (SB/S2/RJN-006/2014) to A.S., and the Spanish Ministry of Economy and Competitiveness (AGL2017-87415-R) to J.J.G.
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Salmonella typhimurium ,0301 basic medicine ,Kinase ,Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Shigella::Shigella flexneri [Medical Subject Headings] ,Swine ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Adaptor Proteins, Signal Transducing::Retinoblastoma Binding Proteins::E2F1 Transcription Factor [Medical Subject Headings] ,General Physics and Astronomy ,Apoptosis ,Diseases::Bacterial Infections and Mycoses::Bacterial Infections::Gram-Negative Bacterial Infections::Enterobacteriaceae Infections::Salmonella Infections [Medical Subject Headings] ,Shigella flexneri ,0302 clinical medicine ,Salmonella ,Endothelial-cells ,Bystander effect ,E2F1 ,RNA-Seq ,HMGB1 Protein ,MicroARNs ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Endoplasmic Reticulum Stress [Medical Subject Headings] ,Multidisciplinary ,Endoplasmic Reticulum Stress ,Cell biology ,Messenger-rna ,030220 oncology & carcinogenesis ,Er stress ,Host-Pathogen Interactions ,Salmonella Infections ,miRNAs ,Pathogens ,Reprogramming ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Communication::Bystander Effect [Medical Subject Headings] ,Endoplasmic-reticulum stress ,Patógenos ,MAP Kinase Signaling System ,Science ,Infecciones por Salmonella ,Activation ,Down-Regulation ,Protein Serine-Threonine Kinases ,Biology ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction::MAP Kinase Signaling System [Medical Subject Headings] ,Article ,General Biochemistry, Genetics and Molecular Biology ,Transmembrane protein ,03 medical and health sciences ,Downregulation and upregulation ,Endoribonucleases ,microRNA ,Animals ,Humans ,Secretion ,Cellular microbiology ,Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Salmonella::Salmonella enterica::Salmonella typhimurium [Medical Subject Headings] ,Hmgb1 ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings] ,Endoplasmic reticulum ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Endonucleases::Endoribonucleases [Medical Subject Headings] ,Bystander Effect ,General Chemistry ,Bacterial pathogenesis ,biology.organism_classification ,Listeria monocytogenes ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases [Medical Subject Headings] ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Organisms::Bacteria::Gram-Positive Bacteria::Bacillales::Listeria::Listeria monocytogenes [Medical Subject Headings] ,Transcription factor ,Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::HeLa Cells [Medical Subject Headings] ,E2F1 Transcription Factor ,HeLa Cells - Abstract
Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection., Cells infected with pathogens can release signals that instruct neighbouring cells to mount an immune response or that reduce these cells’ susceptibility to infection. Here, Aguilar et al. show the opposite effect: cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells by activating their ER-stress response.
- Published
- 2021