A unique PE_PGRS protein inhibiting host cell cytosolic defenses and sustaining full virulence of Mycobacterium marinum in multiple hosts |
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| Authors: | Vipul K. Singh Laurence Berry Audrey Bernut Shubhra Singh Séverine Carrère‐Kremer Albertus Viljoen Laeticia Alibaud Laleh Majlessi Roland Brosch Vinita Chaturvedi Jeroen Geurtsen Michel Drancourt Laurent Kremer |
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| Affiliation: | 1. Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, Université de Montpellier, Montpellier Cedex 05, France;2. Centre d'étude des Pathogènes et Biotechnologies pour la Santé (CPBS), CNRS FRE 3689, Montpellier, France;3. Biochemistry Division, CSIR‐Central Drug Research Institute, Lucknow, Uttar Pradesh, India;4. IFTM University, Lodhipur Rajput, Uttar Pradesh, India;5. INSERM U1058, Université de Montpellier and Department of Bacteriology–Virology, CHU de Montpellier, Montpellier, France;6. Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, Paris, France;7. Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands;8. Université Aix‐Marseille, URMITE, UMR63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France;9. INSERM, CPBS, Montpellier, France |
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| Abstract: | Despite intense research, PE_PGRS proteins still represent an intriguing aspect of mycobacterial pathogenesis. These cell surface proteins influence virulence in several pathogenic species, but their diverse and exact functions remain unclear. Herein, we focussed on a PE_PGRS member from Mycobacterium marinum, MMAR_0242, characterized by an extended and unique C‐terminal domain. We demonstrate that an M. marinum mutant carrying a transposon insertion in MMAR_0242 is highly impaired in its ability to replicate in macrophages and amoebae, because of its inability to inhibit lysosomal fusion. As a consequence, this mutant failed to survive intracellularly as evidenced by a reduced number of cytosolic actin tail‐forming bacteria and by quantitative electron microscopy, which mainly localized MMAR_0242::Tn within membrane‐defined vacuoles. Functional complementation studies indicated that the C‐terminus, but not the N‐terminal PE_PGRS domain, is required for intracellular growth/survival. In line with these findings, disruption of MMAR_0242 resulted in a highly attenuated virulence phenotype in zebrafish embryos, characterized by restricted bacterial loads and a failure to produce granulomas. Furthermore, expression of MMAR_0242 in Mycobacterium smegmatis, a non‐pathogenic species naturally deficient in PE_PGRS production, resulted in increased survival in amoebae with enhanced cytotoxic cell death and increased survival in infected mice with splenomegaly. Overall, these results indicate that MMAR_0242 is required for full virulence of M. marinum and sufficient to confer pathogenic properties to M. smegmatis. |
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