Abstract
BackgroundM. tuberculosis infection either induces or inhibits host cell death, depending on the bacterial strain and the cell microenvironment. There is evidence suggesting a role for mitochondria in these processes.On the other hand, it has been shown that several bacterial proteins are able to target mitochondria, playing a critical role in bacterial pathogenesis and modulation of cell death. However, mycobacteria–derived proteins able to target host cell mitochondria are less studied.ResultsA bioinformaic analysis based on available genomic sequences of the common laboratory virulent reference strain Mycobacterium tuberculosis H37Rv, the avirulent strain H37Ra, the clinical isolate CDC1551, and M. bovis BCG Pasteur strain 1173P2, as well as of suitable bioinformatic tools (MitoProt II, PSORT II, and SignalP) for the in silico search for proteins likely to be secreted by mycobacteria that could target host cell mitochondria, showed that at least 19 M. tuberculosis proteins could possibly target host cell mitochondria. We experimentally tested this bioinformatic prediction on four M. tuberculosis recombinant proteins chosen from this list of 19 proteins (p27, PE_PGRS1, PE_PGRS33, and MT_1866). Confocal microscopy analyses showed that p27, and PE_PGRS33 proteins colocalize with mitochondria.ConclusionsBased on the bioinformatic analysis of whole M. tuberculosis genome sequences, we propose that at least 19 out of 4,246 M. tuberculosis predicted proteins would be able to target host cell mitochondria and, in turn, control mitochondrial physiology. Interestingly, such a list of 19 proteins includes five members of a mycobacteria specific family of proteins (PE/PE_PGRS) thought to be virulence factors, and p27, a well known virulence factor. P27, and PE_PGRS33 proteins experimentally showed to target mitochondria in J774 cells. Our results suggest a link between mitochondrial targeting of M. tuberculosis proteins and virulence.
Highlights
M. tuberculosis infection either induces or inhibits host cell death, depending on the bacterial strain and the cell microenvironment
M. tuberculosis proteins predicted to be secreted and to target host cell mitochondria The whole 4,246 predicted proteins from the M. tuberculosis CDC1551 genome as shown in the JCVI/CMR webpage were analyzed for the presence of mitochondrial targeting sequences by using the MitoProt II– v1.101 algorithm
These analyses showed that the percentage of similarity among the identified M. tuberculosis CDC1551 strain Prolin–Glutamic acid motif (PE) or PE_PGRS proteins and their H37Ra, H37Rv, and BCG Pasteur strain homologous proteins ranged from 53.4% to 81.9%
Summary
M. tuberculosis infection either induces or inhibits host cell death, depending on the bacterial strain and the cell microenvironment. It has been shown that several bacterial proteins are able to target mitochondria, playing a critical role in bacterial pathogenesis and modulation of cell death. The selection and spread of multidrug–resistant (MDR) Mycobacterium tuberculosis strains worsen the. In this regard, some bacterial pathogenicity factors have been shown to contain N–terminal mitochondrial targeting signals [2,3] and a diverse array of bacterial proteins including some bacterial toxins from enteropathogenic E.coli. The M. tuberculosis protein PE_PGRS33 was shown to localize within host cell mitochondria, and in doing so, induces host cell apoptosis [9]
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