Consequence of enhanced LC3-trafficking for a live,attenuated M. tuberculosis vaccine |
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| Institution: | 1. Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA;2. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA;3. Division of Infectious Diseases, Department of Medicine, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA;1. Health Promotion Research Centre, School of Public Health, Zahedan University of Medical Sciences, Zahedan, Iran;2. Centre for Communicable Diseases Control, Ministry of Health and Medical Education, Tehran, Iran;3. Research Center for Infectious Disease and Tropical Medicine, Zahedan University of Medical Sciences, Zahedan, Iran;4. National Reference Laboratory for Measles and Rubella, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran;1. Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, United States;2. Emory University, Atlanta, GA, United States;3. Kid Risk, Inc. and University of Central Florida College of Medicine, Orlando, FL, United States;1. Tianjin Children''s Hospital, Tianjin 300074;2. Division of Infectious Disease and Gastroenterology, Children''s Hospital, Chongqing Medical University, Chongqing 400014;3. Department of Epidemiology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149;4. National Tuberculosis Clinical Lab of China, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149;5. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101;6. Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149;7. Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, Zhejiang;8. Clinical Epidemiology Unit, Peking Union Medical College, Beijing 101149, China;1. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China;2. Institute of Animal Husbandry and Veterinary Sciences, Hubei Academy of Agricultural Sciences, Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture), Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Wuhan, Hubei 430064, China;3. State Key Laboratory of Agricultural Microbiology, The Cooperative Innovation Center for Sustainable Pig Production, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei 430070, China;4. College of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, China;1. Microbial Pathogenesis and Immunity Group, Department of Infectious Diseases and Immunology, University of Sydney, NSW, Australia;2. Mycobacterial Research Program, Centenary Institute, Newtown, NSW, Australia;3. Discipline of Medicine, Central Clinical School, Sydney Medical School, University of Sydney, NSW, Australia |
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| Abstract: | Development of a new vaccine against tuberculosis is urgently needed. Recent work has demonstrated that two related LC3-associated trafficking pathways, autophagy and LC3-associated phagocytosis (LAP), enhance antigen presentation and might play a role in vaccine efficacy. Mycobacterium tuberculosis inhibits both LC3-trafficking pathways. Moreover, the vaccine strain, BCG, induces even less LC3-trafficking than M. tuberculosis, which may help explain its limited efficacy. To determine whether enhanced LC3-trafficking can improve efficacy of a live, attenuated M. tuberculosis vaccine, we took advantage of our recent finding that the bacterial virulence factor CpsA inhibits LAP. When we deleted cpsA in the mc26206 vaccine strain, it dramatically increased LC3-trafficking. We compared the protective efficacy of the strain lacking cpsA to the parent strain and to BCG in mice challenged with M. tuberculosis. We found that the strain lacking cpsA generated modestly enhanced protection in the spleen, but overall did not outperform BCG. |
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| Keywords: | Tuberculosis BCG Autophagy LC3-associated phagocytosis Innate immunity Live attenuated vaccine Auxotroph |
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