Senescent CD8+ T and NK cells contribute to immunopathogy duting cutaneous leishmaniasis

衰老的 CD8 T 和 NK 细胞导致皮肤利什曼病的免疫病理

• 批准号: MR/T015853/1
• 负责人: Arne Akbar
• 金额: $ 93.31万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT015853%2F1
• 关键词: Senescent; CD8+; NK; cells; contribute

Parasites belonging to the genus Leishmania are among the most diverse of human pathogens, both in terms of geographical distribution and in the variety of clinical syndromes caused by them. Currently, 12 million people are infected worldwide in 88 tropical/subtropical countries, 2 million new infections are reported annually, and 350 million people are under infection risk. In the past decade, the number of cases in endemic areas has increased sharply. In addition, leishmaniasis is spreading to several non-endemic areas of the world due to coinfections with HIV. Control measures currently available are case detection and treatment with drugs, which are expensive, not always available and cannot be self-administered. The problem is further aggravated by the surge of drug resistance parasites necessitating the development of an anti-Leishmania vaccine or other immunological therapies urgent.Research has demonstrated the importance of the immunity in controlling both cutaneous and mucocutaneous leishmaniasis, however the severe skin lesions that develop at the infected site is largely due to non-specific tissue damage but the reasons for this are unclear. The majority of this work has been performed on blood samples taken from patients and not from the site of infection at the skin. In this context, a unique feature of the current proposal is that we will be investigating the blood as well as the skin from the same patients, taken from both lesional and non-lesional sites. The main hypothesis of this grant application is that the severity of cutaneous immunopathology in infected individuals is due to non-specific damage mediated by both two types of immune cell namely the natural killer (NK) cells and a type of T cell that represent the "Dad's Army" of the immune system. Both these cell types are probably not triggered by the parasite in the skin lesions, instead they recognize decoy molecules in non-infected skin cells that cause them to be destroyed. This results in the large skin lesions that contain few parasites but huge numbers of dangerous white cells. In this study we will investigate the nature of the white cells in the skin lesions of patients. We will identify the decoy receptors that promote the non-specific tissue damage. We will also look at the wide array of genes that are activated in the skin to identify clue of how the interactions between the immune system and the skin are organized. We will also identify genes that will give us clues as to what other processes may be occurring that do not allow the lesions to resolve. In other parts of the study we will mimic the interaction of cell that are in the skin by growing them in a test tube to probe their interactions and find a way to block them. Finally we will investigate the involvement of a set off molecules known as sestrins, that we previously showed were involved in setting up the decoy mechanisms that may lead to skin lesion formation in patients with cutaneous leishmaniasis.As added value to this proposal, The Federal University of Espirito Santo will contribute 1 Technician and 1 PhD student to work on aspects of this grant.

属于利什曼原虫属的寄生虫是人类病原体中最多样化的，无论是在地理分布方面还是在由它们引起的各种临床综合征方面。目前，全世界88个热带/亚热带国家有1 200万人感染，每年报告200万新感染病例，3.5亿人面临感染风险。在过去十年中，流行地区的病例数量急剧增加。此外，由于与艾滋病毒合并感染，利什曼病正在向世界上几个非流行地区蔓延。目前可用的控制措施是病例检测和药物治疗，但费用昂贵，并非总是可用，而且不能自我管理。由于抗药性寄生虫的激增，使抗利什曼原虫疫苗或其他免疫疗法的开发成为必要，这一问题进一步恶化。研究表明，免疫在控制皮肤和皮肤粘膜利什曼病中的重要性，然而，在感染部位发生的严重皮肤病变主要是由于非特异性组织损伤，但原因尚不清楚。这项工作的大部分是在从患者身上采集的血液样本上进行的，而不是从皮肤感染部位采集的。在这种情况下，当前提案的一个独特特征是，我们将研究来自同一患者的血液和皮肤，从病变和非病变部位采集。该资助申请的主要假设是，受感染个体的皮肤免疫病理学的严重性是由于两种类型的免疫细胞介导的非特异性损伤，即自然杀伤（NK）细胞和代表免疫系统的“爸爸的军队”的T细胞。这两种细胞类型可能不是由皮肤病变中的寄生虫触发的，而是它们识别未感染皮肤细胞中的诱饵分子，导致它们被破坏。这导致了大的皮肤病变，其中含有很少的寄生虫，但大量的危险的白色细胞。在这项研究中，我们将调查的性质，白色细胞在皮肤病变的患者。我们将鉴定促进非特异性组织损伤的诱饵受体。我们还将研究皮肤中被激活的各种基因，以确定免疫系统和皮肤之间的相互作用是如何组织的。我们还将确定基因，这将为我们提供线索，以了解可能发生的其他过程，不允许病变解决。在研究的其他部分，我们将通过在试管中培养细胞来模拟皮肤中细胞的相互作用，以探测它们的相互作用并找到阻止它们的方法。最后，我们将调查的参与，一套小康分子被称为sestrins，我们以前表明参与设置的诱饵机制，可能导致皮肤利什曼病患者皮肤病变的形成。作为附加值，这项建议，圣埃斯皮里托的联邦大学将提供1名技术员和1名博士生工作的方面，这项赠款。

项目成果

Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.

皮肤利什曼病皮肤病变的转录组学景观揭示了与免疫病理学相关的强烈 CD8 T 细胞免疫衰老特征。

• DOI: 10.1111/imm.13410
• 发表时间: 2021
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Fantecelle CH

The role of senescent T cells in immunopathology.

衰老T细胞在免疫病理学中的作用。

• DOI: 10.1111/acel.13272
• 发表时间: 2020-12
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Covre LP;De Maeyer RPH;Gomes DCO;Akbar AN
• 通讯作者: Akbar AN

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis.

• DOI: 10.3389/fimmu.2021.632667
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Garcia de Moura R;Covre LP;Fantecelle CH;Gajardo VAT;Cunha CB;Stringari LL;Belew AT;Daniel CB;Zeidler SVV;Tadokoro CE;de Matos Guedes HL;Zanotti RL;Mosser D;Falqueto A;Akbar AN;Gomes DCO
• 通讯作者: Gomes DCO

Sicilian semi- and supercentenarians: identification of age-related T-cell immunophenotype to define longevity trait

• DOI: 10.1093/cei/uxad074
• 发表时间: 2023-12-11
• 期刊: CLINICAL AND EXPERIMENTAL IMMUNOLOGY
• 影响因子: 4.6
• 作者: Ligotti，Mattia Emanuela;Accardi，Giulia;Candore，Giuseppina
• 通讯作者: Candore，Giuseppina