Deletion of zmp1 improves Mycobacterium bovis BCG-mediated protection in a guinea pig model of tuberculosis |
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| Affiliation: | 1. Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland;2. Nationales Zentrum für Mykobakterien, Gloriastrasse 30/32, 8006 Zurich, Switzerland;3. Microbiology Services, Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom;4. Unitat de Tuberculosi Experimental, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autonoma de Barcelona, CIBERES, Badalona, Catalonia, Spain;5. Deptartment of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom;6. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland;1. Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y diseño del Estado de Jalisco, A.C., Av. Normalistas No. 800, Col. Colinas de la Normal, 44270 Guadalajara, Jalisco, Mexico;2. Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Tlalpan, México, D.F. 14000, Mexico;1. Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France;2. Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy;3. Public Health England, Porton Down, Salisbury, Wiltshire, United Kingdom;4. London School of Hygiene and Tropical Medicine, London, United Kingdom;5. Laboratory of Pediatric Infectious Diseases, Radboud University Medical Center Nijmegen, The Netherlands;6. Université de Lille, Institut Pasteur de Lille, Inserm U1019, CNRS UMR8204, France;1. Max Planck Institute for Infection Biology, Department of Immunology, Charitéplatz 1, 10117 Berlin, Germany;2. National University of Singapore, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, 5 Science Drive 2, Block MD4, Level 3, Singapore 117545, Singapore;1. Animal & Plant Health Agency (APHA), Woodham Lane, Addlestone KT15 3NB, United Kingdom;2. Current address: Orbio Laboratoire, 12C rue du 35eme Regiment d''Aviation, 69500 Bron, France;1. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai 200438, People''s Republic of China;2. Medical College, Hexi University, Zhangye, Gansu 734000, People''s Republic of China;3. Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People''s Republic of China;4. Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People''s Republic of China;5. Shanghai Pulmonary Hospital, Medical School, Tongji University, Shanghai 200433, People''s Republic of China;1. Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, US;2. Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, US |
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| Abstract: | Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials. |
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| Keywords: | Tuberculosis BCG Protection Safety Live vaccine Protease Guinea pig |
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