Translocon-independent intracellular replication by Pseudomonas aeruginosa requires the ADP-ribosylation domain of ExoS |
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| Authors: | Victoria Hritonenko David J Evans Suzanne MJ Fleiszig |
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| Institution: | 1. School of Optometry, University of California, Berkeley, CA 94720, USA;2. College of Pharmacy, Touro University California, Vallejo, CA 94592, USA;3. Graduate Groups in Vision Sciences, Microbiology, and Infectious Diseases & Immunity, University of California, Berkeley, CA 94720, USA;1. Instituto René Rachou-FIOCRUZ, Avenida Augusto de Lima 1715, Belo Horizonte, Minas Gerais, Brazil;2. Department of Microbiology, Immunology & Tropical Medicine, George Washington University Medical Center, 2300 Eye Street, NW, Washington, DC 20037, USA;1. Frontage Clinical Research Center, 241 Main Street, 3rd Floor, Hackensack, NJ 07601, USA;2. Pfizer Vaccine Research, 500 Arcola Rd, Collegeville, PA 19426, USA;3. Pfizer Vaccine Research, 401 N Middletown Rd , Pearl River, NY 10965, USA;4. Pfizer Medical and Scientific Affairs, 500 Arcola Rd, Collegeville, PA 19426, USA;1. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;2. Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;3. Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;4. Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain;1. Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 5164, 33000 Bordeaux, France;2. University of Bordeaux, Bordeaux, France;3. Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands;1. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States;2. Dana-Farber Cancer Institute, Boston, MA, United States;3. University of Wisconsin, Madison, WI, United States;4. Hospital Madrid Sanchinarro, Madrid, Spain;5. University of Pittsburgh, Pittsburgh, PA, United States;6. Decatur Memorial Hospital, Decatur, IL, United States;7. Northwestern University, Chicago, IL, United States;8. Sanford Cancer Center, Sioux Falls, SD, United States;9. University of Texas Southwestern Medical Center, Dallas, TX, United States |
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| Abstract: | Pseudomonas aeruginosa, a significant cause of human morbidity and mortality, uses a type 3 secretion system (T3SS) to inject effector toxins into host cells. We previously reported that P. aeruginosa uses ADP-ribosyltransferase (ADPr) activity of the T3SS effector ExoS for intracellular replication. T3SS translocon (ΔpopB)-mutants, which can export, but not translocate effectors across host membranes, retained intracellular replication. We hypothesized that secreted effectors mediate translocon-independent intracellular replication. Translocon mutants of PAO1 lacking one or more of its three known effectors (ExoS, ExoT and ExoY) were used. All translocon mutants, irrespective of effectors expressed, localized to intracellular vacuoles. Translocon-effector null mutants and translocon-exoS mutants showed defective intracellular replication. Mutants in exoT, exoY or both replicated as efficiently as translocon mutants expressing all effectors. Complementation of translocon-effector null mutants with native exoS or a membrane localization domain mutant of exoS, but not the ADPr mutant exoS (pUCPexoSE381D), restored intracellular replication, correlating with increased bacteria per vacuole. Thus, P. aeruginosa is capable of intravacuolar replication that requires ExoS ADPr activity, but not the translocon. These data suggest that T3SS effectors can participate in pathogenesis without translocon-mediated translocation across host membranes, and that intracellular bacteria can contribute to P. aeruginosa pathogenesis within epithelial cells. |
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