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寄生虫，无论是在地理分布和由其引起的临床综合症的种类方面。目前，在88个热带/亚热带国家中，全世界有1,200万人被感染，每年有200万新的感染，3.5亿人受感染风险。在过去的十年中，地方性地区的案件数量急剧增加。此外，由于与艾滋病毒的共同感染，利什曼病正在扩散到世界上几个非流行地区。当前可用的控制措施是用药物检测和治疗，这些药物很昂贵，并不总是可用，不能自我管理。抗药性寄生虫的激增需要开发抗leishmania疫苗或其他免疫学疗法，这进一步加剧了问题。研究表明，免疫在控制皮肤和毛状眼皮术和粘膜胶质性利什玛病中的重要性，但是由于受感染而导致的严重皮肤病变是不受特征性的损害，但要损害了该部位的特定性，但损害了特定的特征。这项工作的大部分是针对从患者而不是从皮肤感染部位采集的血液样本进行的。在这种情况下，当前提案的一个独特特征是，我们将研究来自病变和非静态部位的同一患者的血液以及同一患者的皮肤。该赠款应用的主要假设是，受感染个体的皮肤免疫病理学的严重程度是由于两种免疫细胞介导的非特异性损害，即自然杀伤剂（NK）细胞（NK）细胞和代表免疫系统的“爸爸军”的一种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，而是识别未感染的皮肤细胞中的诱饵分子，导致它们被破坏。这导致较大的皮肤病变含有很少的寄生虫，但大量危险的白细胞。在这项研究中，我们将研究患者皮肤病变中白细胞的性质。我们将确定诱导非特异性组织损伤的诱饵受体。我们还将研究在皮肤中激活的各种基因，以识别免疫系统与皮肤之间如何组织相互作用的线索。我们还将确定将为我们提供有关其他过程可能不允许病变解决的基因。在研究的其他部分，我们将通过在试管中种植它们来探测它们的相互作用并找到阻止它们的方法来模仿皮肤中细胞的相互作用。最后，我们将研究一个称为sestrins的分子的参与，我们先前表明的参与了可能导致皮肤利什曼病的患者的皮肤病变形成的诱饵机制。由于该提案的增加价值，Espirito Santo联邦大学将贡献1名技术人员和1名PHD学生，从而在该方面工作。

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

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

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

The role of senescent T cells in immunopathology.

• 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

Senescent T cells: Beneficial and detrimental roles

• DOI: 10.1111/imr.13206
• 发表时间: 2023-04-25
• 期刊: IMMUNOLOGICAL REVIEWS
• 影响因子: 8.7
• 作者: Laphanuwat，Phatthamon;Gomes，Daniel Claudio Oliveira;Akbar，Arne N.
• 通讯作者: Akbar，Arne N.