Majlessi Laleh, Brodin Priscille, Brosch Roland, Rojas Marie-Jésus, Khun Huot, Huerre Michel, Cole Stewart T, Leclerc Claude
Unité de Biologie des Régulations Immunitaires, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale Equipe 352, Paris, France.
J Immunol. 2005 Mar 15;174(6):3570-9. doi: 10.4049/jimmunol.174.6.3570.
The chromosomal locus encoding the early secreted antigenic target, 6 kDa (ESAT-6) secretion system 1 of Mycobacterium tuberculosis, also referred to as "region of difference 1 (RD1)," is absent from Mycobacterium bovis bacillus Calmette-Guerin (BCG). In this study, using low-dose aerosol infection in mice, we demonstrate that BCG complemented with RD1 (BCG::RD1) displays markedly increased virulence which albeit does not attain that of M. tuberculosis H37Rv. Nevertheless, phenotypic and functional analyses of immune cells at the site of infection show that the capacity of BCG::RD1 to initiate recruitment/activation of immune cells is comparable to that of fully virulent H37Rv. Indeed, in contrast to the parental BCG, BCG::RD1 mimics H37Rv and induces substantial influx of activated (CD44highCD45RB(-)CD62L(-)) or effector (CD45RB(-)CD27(-)) T cells and of activated CD11c(+)CD11bhigh cells to the lungs of aerosol-infected mice. For the first time, using in vivo analysis of transcriptome of inflammatory cytokines and chemokines of lung interstitial CD11c+ cells, we show that in a low-dose aerosol infection model, BCG::RD1 triggered an activation/inflammation program comparable to that induced by H37Rv while parental BCG, due to its overattenuation, did not initiate the activation program in lung interstitial CD11c+ cells. Thus, products encoded by the ESAT-6 secretion system 1 of M. tuberculosis profoundly modify the interaction between mycobacteria and the host innate and adaptive immune system. These modifications can explain the previously described improved protective capacity of BCG::RD1 vaccine candidate against M. tuberculosis challenge.
编码结核分枝杆菌早期分泌性抗原靶标6千道尔顿（ESAT-6）分泌系统1的染色体位点，也被称为“差异区域1（RD1）”，在卡介苗（BCG）中不存在。在本研究中，我们通过对小鼠进行低剂量气溶胶感染，证明补充了RD1的卡介苗（BCG::RD1）毒力显著增加，尽管未达到结核分枝杆菌H37Rv的毒力。然而，对感染部位免疫细胞的表型和功能分析表明，BCG::RD1启动免疫细胞募集/激活的能力与完全有毒力的H37Rv相当。事实上，与亲本卡介苗不同，BCG::RD1模拟H37Rv，诱导活化的（CD44高CD45RB（-）CD62L（-））或效应性（CD45RB（-）CD27（-））T细胞以及活化的CD11c（+）CD11b高细胞大量流入气溶胶感染小鼠的肺部。首次通过对肺间质CD11c+细胞炎性细胞因子和趋化因子转录组进行体内分析，我们表明在低剂量气溶胶感染模型中，BCG::RD1引发了与H37Rv诱导的相当的激活/炎症程序，而亲本卡介苗由于过度减毒，未在肺间质CD11c+细胞中启动激活程序。因此，结核分枝杆菌ESAT-6分泌系统1编码的产物深刻改变了分枝杆菌与宿主固有和适应性免疫系统之间的相互作用。这些改变可以解释先前描述的BCG::RD1候选疫苗对结核分枝杆菌攻击的保护能力提高。
