New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles.
New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles.
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DOI：
10.1038/srep37793
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发表时间：
2016-11-28
影响因子：
4.6
通讯作者：
Ottenhoff TH
中科院分区：
文献类型：
--
作者：
Coppola M;van Meijgaarden KE;Franken KL;Commandeur S;Dolganov G;Kramnik I;Schoolnik GK;Comas I;Lund O;Prins C;van den Eeden SJ;Korsvold GE;Oftung F;Geluk A;Ottenhoff TH
需要新的战略来开发更好的工具来控制结核病，包括识别用于疫苗接种的新抗原。在结核分枝杆菌感染期间，这种结核分枝杆菌抗原必须在主要的靶器官肺中表达，并且必须能够激发人类的免疫反应。利用结核分枝杆菌感染肺的全基因组转录组学，我们开发了数据集和方法来鉴定在肺中表达的IVE-TB(体内表达的结核分枝杆菌)抗原。对预测的第一操纵子的2,068个Mtb基因的定量表达分析确定了体内肺部感染期间上调最多的IVE-TB基因。通过进一步分析全基因组测序结核分枝杆菌复合体株(N HLA219)之间的高度保守性和预测 = -Ia和II类呈现表位的算法，我们选择了最有希望的IVE-TB候选抗原。其中一些是由体外Mtb-PPD和ESAT6/CFP10阳性供者的T细胞通过增殖和产生多种细胞因子识别的。这在一组潜伏感染结核分枝杆菌的独立队列中得到了验证。在不产生干扰素-γ的情况下，观察到显著的T细胞反应。总而言之，这些结果强调了我们新的抗原发现方法在识别结核分枝杆菌抗原方面的力量，包括那些诱导非传统T细胞反应的抗原，这可能为结核病疫苗接种和生物标记物分析提供重要的新工具。我们的通用方法也适用于其他传染病。
New strategies are needed to develop better tools to control TB, including identification of novel antigens for vaccination. Such Mtb antigens must be expressed during Mtb infection in the major target organ, the lung, and must be capable of eliciting human immune responses. Using genome-wide transcriptomics of Mtb infected lungs we developed data sets and methods to identify IVE-TB (in-vivo expressed Mtb) antigens expressed in the lung. Quantitative expression analysis of 2,068 Mtb genes from the predicted first operons identified the most upregulated IVE-TB genes during in-vivo pulmonary infection. By further analysing high-level conservation among whole-genome sequenced Mtb-complex strains (n = 219) and algorithms predicting HLA-class-Ia and II presented epitopes, we selected the most promising IVE-TB candidate antigens. Several of these were recognized by T-cells from in-vitro Mtb-PPD and ESAT6/CFP10-positive donors by proliferation and multi-cytokine production. This was validated in an independent cohort of latently Mtb-infected individuals. Significant T-cell responses were observed in the absence of IFN-γ-production. Collectively, the results underscore the power of our novel antigen discovery approach in identifying Mtb antigens, including those that induce unconventional T-cell responses, which may provide important novel tools for TB vaccination and biomarker profiling. Our generic approach is applicable to other infectious diseases.
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影响因子：
7.8
作者：
Behar SM;Carpenter SM;Booty MG;Barber DL;Jayaraman P
通讯作者：
Jayaraman P
DOI：
10.1016/j.tube.2015.07.001
发表时间：
2015-12
期刊：
Tuberculosis (Edinburgh, Scotland)
影响因子：
--
作者：
Carpenter C;Sidney J;Kolla R;Nayak K;Tomiyama H;Tomiyama C;Padilla OA;Rozot V;Ahamed SF;Ponte C;Rolla V;Antas PR;Chandele A;Kenneth J;Laxmi S;Makgotlho E;Vanini V;Ippolito G;Kazanova AS;Panteleev AV;Hanekom W;Mayanja-Kizza H;Lewinsohn D;Saito M;McElrath MJ;Boom WH;Goletti D;Gilman R;Lyadova IV;Scriba TJ;Kallas EG;Murali-Krishna K;Sette A;Lindestam Arlehamn CS
通讯作者：
Lindestam Arlehamn CS
影响因子：
3.1
作者：
Duthie, Malcolm S.;Coler, Rhea N.;Reed, Steven G.
通讯作者：
Reed, Steven G.
影响因子：
5.4
作者：
Caccamo, Nadia;Guggino, Giuliana;Dieli, Francesco
通讯作者：
Dieli, Francesco
影响因子：
6.7
作者：
Lindestam Arlehamn CS;Gerasimova A;Mele F;Henderson R;Swann J;Greenbaum JA;Kim Y;Sidney J;James EA;Taplitz R;McKinney DM;Kwok WW;Grey H;Sallusto F;Peters B;Sette A
通讯作者：
Sette A