| Autor: |
Orgeur M; Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris 75015, France., Frigui W; Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris 75015, France., Pawlik A; Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris 75015, France., Clark S; Public Health England, Porton Down, Salisbury SP4 0JG, UK., Williams A; Public Health England, Porton Down, Salisbury SP4 0JG, UK., Ates LS; Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris 75015, France.; Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Meibergdreef 9, Amsterdam, Netherlands., Ma L; Institut Pasteur, Biomics, C2RT, Paris 75015, France., Bouchier C; Institut Pasteur, Biomics, C2RT, Paris 75015, France., Parkhill J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.; Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK., Brodin P; CIIL - Center for Infection and Immunity of Lille, Université de Lille/CNRS UMR 9017/INSERM U1019/CHU Lille/Institut Pasteur de Lille, Lille 59000, France., Brosch R; Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris 75015, France. |
| Abstrakt: |
Mycobacterium microti is an animal-adapted member of the Mycobacterium tuberculosis complex (MTBC), which was originally isolated from voles, but has more recently also been isolated from other selected mammalian hosts, including occasionally from humans. Here, we have generated and analysed the complete genome sequences of five representative vole and clinical M. microti isolates using PacBio- and Illumina-based technologies, and have tested their virulence and vaccine potential in SCID (severe combined immune deficient) mouse and/or guinea pig infection models. We show that the clinical isolates studied here cluster separately in the phylogenetic tree from vole isolates and other clades from publicly available M. microti genome sequences. These data also confirm that the vole and clinical M. microti isolates were all lacking the specific RD1 mic region, which in other tubercle bacilli encodes the ESX-1 type VII secretion system. Biochemical analysis further revealed marked phenotypic differences between isolates in type VII-mediated secretion of selected PE and PPE proteins, which in part were attributed to specific genetic polymorphisms. Infection experiments in the highly susceptible SCID mouse model showed that the clinical isolates were significantly more virulent than the tested vole isolates, but still much less virulent than the M. tuberculosis H37Rv control strain. The strong attenuation of the ATCC 35872 vole isolate in immunocompromised mice, even compared to the attenuated BCG (bacillus Calmette-Guérin) vaccine, and its historic use in human vaccine trials encouraged us to test this strain's vaccine potential in a guinea pig model, where it demonstrated similar protective efficacy as a BCG control, making it a strong candidate for vaccination of immunocompromised individuals in whom BCG vaccination is contra-indicated. Overall, we provide new insights into the genomic and phenotypic variabilities and particularities of members of an understudied clade of the MTBC, which all share a recent common ancestor that is characterized by the deletion of the RD1 mic region. |
