An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology
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An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology. / Clemmensen, Helena Strand; Knudsen, Niels Peter Hell; Rasmussen, Erik Michael; Winkler, Jessica; Rosenkrands, Ida; Ahmad, Ahmad; Lillebaek, Troels; Sherman, David R.; Andersen, Peter Lawætz; Aagaard, Claus.
In: Scientific Reports, Vol. 7, 46666, 2017.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology
AU - Clemmensen, Helena Strand
AU - Knudsen, Niels Peter Hell
AU - Rasmussen, Erik Michael
AU - Winkler, Jessica
AU - Rosenkrands, Ida
AU - Ahmad, Ahmad
AU - Lillebaek, Troels
AU - Sherman, David R.
AU - Andersen, Peter Lawætz
AU - Aagaard, Claus
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1038/srep46666
DO - 10.1038/srep46666
M3 - Journal article
C2 - 28436493
AN - SCOPUS:85038947538
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 46666
ER -
ID: 247161195