Abstract
Although Mycobacterium tuberculosis (M.tb) DK9897 is an attenuated strain, it was isolated from a patient with extrapulmonary tuberculosis and vaccination with a subunit vaccine (H56) induced poor protection against it. Both attenuation and lack of protection are because M.tb DK9897 cannot secrete the EsxA virulence factor nor induce a host response against it. Genome sequencing identified a frameshift mutation in the eccCa1 gene. Since the encoded EccCa1 protein provides energy for ESX-1 secretion, it suggested a defect in the ESX-1 type VII secretion system. Genetic complementation with a plasmid carrying the M.tb H37Rv sequence of eccCa1-eccCb1-pe35 re-established EsxA secretion, host specific EsxA T-cell responses, and increased strain virulence. The ESX-1 secretion defect prevents several virulence factors from being functional during infection and therefore attenuates M.tb. It precludes specific T-cell responses against strong antigens and we found very little in vivo cytokine production, gross pathology or granuloma formation in lungs from M.tb DK9897 infected animals. This coincides with M.tb DK9897 being unable to disrupt the phagosome membrane and make contact to the cytosol.
Highlights
M.tb exploits the ESX-1 type VII secretion system to secrete virulence factors that are involved in survival and spreading of the pathogen via interactions with the host cells[10,11]
Two most recent studies demonstrate that EsxA is not directly responsible for membrane lysis, rather this activity is attributed to ESX-1 in concert with phthiocerol dimycocerosates (DIMs) and is contact dependent, which results in gross membrane disruptions rather than pore formation[22,23]
One quick and reliable marker commonly used for M.tb genotyping is the mycobacterial interspersed repetitive units (MIRU), located in variable number tandem repeats (VNTR) found at multiple loci scattered throughout the genome
Summary
M.tb exploits the ESX-1 type VII secretion system to secrete virulence factors that are involved in survival and spreading of the pathogen via interactions with the host cells[10,11]. Comparative analysis of genomes from attenuated M. bovis BCG strains and pathogenic mycobacterial species identified the main chromosomal ESX-1 locus, containing region of difference 1 (RD1) genes, and showed that this region encodes the immunodominant T cell antigens EsxA (ESAT-6) and EsxB (CFP-10)[12,13,14]. EsxA has been reported to be involved in numerous biological processes relevant for virulence including; initiation of granuloma formation[17], phagosome maturation[18,19], apoptosis through caspase activation[20] and induction of membrane damage and phagosomal disruption[21]. We report on the initial characterization of this clinical isolate and the responses it induces in the host during infection
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