Abstract
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 RD1mic 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 RD1mic region.
Highlights
Within the Mycobacterium tuberculosis complex (MTBC), Mycobacterium microti is one of the earliest described members and belongs to the animal-adapted lineage [1, 2]
Further database comparisons showed that the remaining sixth spacer of this region was only detected in a few strains of TbD1-intact M. tuberculosis and Mycobacterium africanum strains, as well as in M. microti ATCC 19422, which is consistent with a previous study that focused on the direct repeat (DR) locus of MTBC members [83]
Strain ATCC 35782 harboured additional spacers and repeats, as compared to the other M. microti strains, for which half of them were identical to the ones found in M. tuberculosis H37Rv (Fig. 1b), whereas others were mainly detected in TbD1-intact M. tuberculosis, M. africanum, M. bovis and BCG vaccine strains, in agreement with previous spoligotyping studies [17, 30, 83]
Summary
Within the Mycobacterium tuberculosis complex (MTBC), Mycobacterium microti is one of the earliest described members and belongs to the animal-adapted lineage [1, 2]. Many of these additional host species might represent spillover infections potentially linked to rodents, especially for cats [7], which might occur from environmental contamination via sputum and saliva, or direct contact through skin lesion, bite or feeding [14]
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