Bacteria modulate the CD8+ T cell epitope repertoire of host cytosol-exposed proteins to manipulate the host immune response.
Bacteria modulate the CD8+ T cell epitope repertoire of host cytosol-exposed proteins to manipulate the host immune response.
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DOI：
10.1371/journal.pcbi.1002220
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Louzoun Y
中科院分区：
文献类型：
--
作者：
Maman Y;Nir-Paz R;Louzoun Y
对细菌的主要适应性免疫反应是由 B 细胞和 CD4+ T 细胞介导的。然而，一些细菌蛋白到达宿主细胞的细胞质并暴露于宿主 CD8+ T 细胞反应。革兰氏阴性菌和革兰氏阳性菌都可以分别通过 III 型和 IV 型分泌以及 ESX-1 系统将蛋白质转移到胞质溶胶中。易位的蛋白质通常对于细菌的生存至关重要。一旦注射，这些蛋白质就会被降解并以 MHC-I 分子的形式呈递给 CD8+ T 细胞。 CD8+ T 细胞反过来可以诱导细胞死亡并破坏细菌的栖息地。在病毒中，会出现逃逸突变来避免这种检测。细菌中逃逸突变的积累从未被系统地研究过。我们首次表明这种突变系统地存在于大多数测试的细菌中。我们结合多种生物信息学算法来计算细菌的 CD8+ T 细胞表位库，以及将蛋白质易位到宿主细胞质的分泌系统。在所有测试的细菌中，未转位到胞质溶胶的蛋白质在其 CD8+ T 细胞表位中没有显示逃逸突变。然而，易位到胞质溶胶的蛋白质显示出明显的逃逸突变，并且对于大多数测试的 HLA 等位基因来说，表位密度较低。低表位密度表明，细菌和病毒一样，经过进化选择，以确保它们在 CD8+ T 细胞存在的情况下生存。与大多数其他检测到的易位蛋白相比，铜绿假单胞菌的 ExoU（最终诱导宿主细胞死亡）被发现具有高表位密度。这一发现提出了病原体操纵 CD8+ T 细胞的新机制。 ExoU 效应子可能已经进化到维持高表位密度，使其能够有效诱导 CD8+ T 细胞介导的细胞死亡。使用多种表位预测算法对这些结果进行了测试，并且发现对于大多数测试的蛋白质来说是一致的。细菌蛋白主要暴露于 B 细胞和 CD4+ T 细胞，而 CD8+ T 细胞 (CTL) 通常对病毒做出反应。 CTL 对病毒反应的限制是由于呈递给 CTL 的表位的处理途径造成的。这些表位通常源自细胞质中表达的蛋白质。这些蛋白质最终被降解并在 MHC-I 分子上呈递给 CTL。然而，细菌 III 型分泌系统 (T3SS) 效应子也可以进入宿主细胞质，并且也可能受到 CTL 反应。因此，我们可以假设这组蛋白质会针对 CTL 表位的呈现进行选择，如病毒蛋白质中所见。使用多个表位预测算法，我们表明大多数 T3SS 效应子以及单核细胞增生李斯特菌中的 LLO 和 ActA 以及结核分枝杆菌中的 ESAT-6 蛋白都经过系统选择，以减少其表位的数量和质量。这方面的例外是铜绿假单胞菌效应子 ExoU，它具有高密度的高质量表位。由于已知 ExoU 会诱导宿主细胞快速死亡，因此我们假设铜绿假单胞菌利用免疫反应来诱导这种死亡。大肠杆菌表位密度在菌株之间变化很大。
The main adaptive immune response to bacteria is mediated by B cells and CD4+ T-cells. However, some bacterial proteins reach the cytosol of host cells and are exposed to the host CD8+ T-cells response. Both gram-negative and gram-positive bacteria can translocate proteins to the cytosol through type III and IV secretion and ESX-1 systems, respectively. The translocated proteins are often essential for the bacterium survival. Once injected, these proteins can be degraded and presented on MHC-I molecules to CD8+ T-cells. The CD8+ T-cells, in turn, can induce cell death and destroy the bacteria's habitat. In viruses, escape mutations arise to avoid this detection. The accumulation of escape mutations in bacteria has never been systematically studied. We show for the first time that such mutations are systematically present in most bacteria tested. We combine multiple bioinformatic algorithms to compute CD8+ T-cell epitope libraries of bacteria with secretion systems that translocate proteins to the host cytosol. In all bacteria tested, proteins not translocated to the cytosol show no escape mutations in their CD8+ T-cell epitopes. However, proteins translocated to the cytosol show clear escape mutations and have low epitope densities for most tested HLA alleles. The low epitope densities suggest that bacteria, like viruses, are evolutionarily selected to ensure their survival in the presence of CD8+ T-cells. In contrast with most other translocated proteins examined, Pseudomonas aeruginosa's ExoU, which ultimately induces host cell death, was found to have high epitope density. This finding suggests a novel mechanism for the manipulation of CD8+ T-cells by pathogens. The ExoU effector may have evolved to maintain high epitope density enabling it to efficiently induce CD8+ T-cell mediated cell death. These results were tested using multiple epitope prediction algorithms, and were found to be consistent for most proteins tested. Bacterial proteins are mainly exposed to B-cells and CD4+ T-cells, while CD8+ T-cells (CTL) typically respond to viruses. The limitation of the CTL response to viruses results from processing pathways of epitopes presented to CTLs. These epitopes usually stem from proteins expressed in the cytosol. Such proteins are eventually degraded and presented on MHC-I molecules to CTLs. However bacterial Type III secretion system (T3SS) effectors also have an access to the host cytosol and may also be exposed to CTL response. Thus, we can assume that this group of proteins undergoes selection against the presentation of CTL epitopes, as seen in viral proteins. Using multiple epitope prediction algorithms, we show that most T3SS effectors, as well as LLO, and ActA in Listeria monocytogenes and ESAT-6 proteins in Mycobacterium tuberculosis, are systematically selected to reduce the number and quality of their epitopes. The exception in this respect is the Pseudomonas aeruginosa effector ExoU that has high density of high quality epitopes. Since ExoU is known to induce rapid cell death in hosts cells, we assume that P.aeruginosa utilize the immune response to induce such death. The E.coli epitope density is highly variable among strains.
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DOI：
10.1073/pnas.0404740101
发表时间：
2004-09-07
影响因子：
11.1
作者：
Istrail, S;Florea, L;Hoffman, SL
通讯作者：
Hoffman, SL
影响因子：
64.5
作者：
Kenny, B;DeVinney, R;Finlay, BB
通讯作者：
Finlay, BB
影响因子：
5.4
作者：
Almani M;Raffaeli S;Vider-Shalit T;Tsaban L;Fishbain V;Louzoun Y
通讯作者：
Louzoun Y
影响因子：
3.6
作者：
FinckBarbancon, V;Goranson, J;Frank, DW
通讯作者：
Frank, DW
影响因子：
3.6
作者：
Kenny, B;Ellis, S;Jepson, MA
通讯作者：
Jepson, MA