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Dissection of ESAT-6 System 1 of Mycobacterium tuberculosis and Impact on Immunogenicity and Virulence

机译：结核分枝杆菌ESAT-6系统1的解剖及其对免疫原性和毒力的影响

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The dedicated secretion system ESX-1 of Mycobacterium tuberculosis encoded by the extended RD1 region (extRD1) assures export of the ESAT-6 protein and its partner, the 10-kDa culture filtrate protein CFP-10, and is missing from the vaccine strains M. bovis BCG and M. microti. Here, we systematically investigated the involvement of each individual ESX-1 gene in the secretion of both antigens, specific immunogenicity, and virulence. ESX-1-complemented BCG and M. microti strains were more efficiently engulfed by bone-marrow-derived macrophages than controls, and this may account for the enhanced in vivo growth of ESX-1-carrying strains. Inactivation of gene pe35 (Rv3872) impaired expression of CFP-10 and ESAT-6, suggesting a role in regulation. Genes Rv3868, Rv3869, Rv3870, Rv3871, and Rv3877 encoding an ATP-dependent chaperone and translocon were essential for secretion of ESAT-6 and CFP-10 in contrast to ppe68 Rv3873 and Rv3876, whose inactivation did not impair secretion of ESAT-6. A strict correlation was found between ESAT-6 export and the generation of ESAT-6 specific T-cell responses in mice. Furthermore, ESAT-6 secretion and specific immunogenicity were almost always correlated with enhanced virulence in the SCID mouse model. Only loss of Rv3865 and part of Rv3866 did not affect ESAT-6 secretion or immunogenicity but led to attenuation. This suggests that Rv3865/66 represent a new virulence factor that is independent from ESAT-6 secretion. The present study has allowed us to identify new aspects of the extRD1 region of M. tuberculosis and to explore its role in the pathogenesis of tuberculosis.
机译：扩展的RD1区域（extRD1）编码的结核分枝杆菌的专用分泌系统ESX-1确保ESAT-6蛋白及其伴侣，10 kDa培养滤液蛋白CFP-10和疫苗株 M中缺失。 bovis BCG和 M。微量。在这里，我们系统地研究了每个单独的ESX-1基因在两种抗原，特异性免疫原性和毒力分泌中的参与。 ESX-1补充了BCG和 M。相比于对照，骨髓来源的巨噬细胞更容易吞噬微量菌株，这可能是携带ESX-1的菌株体内生长增强的原因。基因 pe35 （Rv3872）失活会破坏CFP-10和ESAT-6的表达，提示其在调节中的作用。与 ppe68 Rv3873和Rv3876失活的 ppe68 Rv3873和Rv3876相比，编码ATP依赖性伴侣和反式转运蛋白的Rv3868，Rv3869，Rv3870，Rv3871和Rv3877基因对于ESAT-6和CFP-10的分泌至关重要。损害ESAT-6的分泌。在小鼠中，ESAT-6的输出与ESAT-6特异性T细胞反应的产生之间存在严格的相关性。此外，在SCID小鼠模型中，ESAT-6的分泌和特异性免疫原性几乎总是与毒力增强相关。仅Rv3865和Rv3866的一部分丢失不会影响ESAT-6的分泌或免疫原性，但会导致减毒。这表明Rv3865 / 66代表了一种新的毒力因子，与ESAT-6分泌无关。本研究使我们能够确定 M的extRD1区域的新方面。结核病及其在结核病发病机理中的作用。

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