Suppression of anti-malarial humoral immune responses by gamaherpesviruses

伽马疱疹病毒抑制抗疟疾体液免疫反应

• 批准号: 9444089
• 负责人: Tracey Jane Lamb
• 金额: $ 39.51万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444089
• 关键词: Acute; Affect; Affinity; Africa South of the Sahara; Age; Alpha Cell; Anemia; Antibodies; Antibody Formation; Antibody Response; Antibody Specificity; Antigens; Antimalarials; B-Lymphocytes; Blood; Capsid; Cells; Cerebral Malaria; Cessation of life; Child; Childhood; Coin; Country; Data; Development; Disease; Epitopes; Epstein-Barr Virus Infections; Event; Falciparum Malaria; Fever; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Hospitalization; Human Herpesvirus 4; Humoral Immunities; Immune; Immune response; Immunity; Immunoglobulin M; Immunosuppression; Immunosuppressive Agents; Impairment; Income; Infant; Infection; Interleukin-10; Knowledge; Laboratories; Life; Longevity; Malaria; Memory; Mission; Monitor; Morals; Outcome; Parasitemia; Parasites; Plasmodium; Plasmodium falciparum; Population; Primary Infection; Proteins; Public Health; Publishing; Research; Risk Factors; Rodent Model; Secondary to; Testing; United States National Institutes of Health; Viral; Virus Diseases; Virus Latency; Work; antigen challenge; clinical development; co-infection; disability; experience; gammaherpesvirus; human disease; infected B cell; innovation; insight; latency-associated protein; malaria infection; mouse model; negative affect; novel; novel therapeutic intervention; prevent; response; seropositive; stem

The humoral response to malaria is critical in the control of blood stage parasitemia and the breadth of the antibody response is protective against the development of clinical malaria. It is not understood why some children fail to develop adequate humoral immune responses to Plasmodium infection early in life. Both Plasmodium falciparum malaria and Epstein Barr virus (EBV) are childhood infections in sub- Saharan Africa. The majority of children become seropositive for EBV within the first years of life, an event that is normally asymptomatic but accompanied by potent immunosuppression. The long term goal of this proposal is to provide mechanistic evidence that overlapping acute gammaherpesvirus coin- fections are responsible for suppressing the development of humoral immunity during Plasmodium in- fection in children. Using well established mouse models of EBV (MHV68) and malaria the objective of this proposal is to identify how the humoral immune response to malaria is altered by an MHV68 la- tency associated protein (M2), and to identify which features of the humoral response are affected (magnitude, breadth, affinity and longevity). The central hypothesis of this proposal is that the induction of IL-10 by M2 in MHV68-infected B cells impairs the ability of T follicular helper cells to provide B cell help for effective, broad spectrum antibody production to incoming Plasmodium infection. This hypothe- sis has been formulated from our published and preliminary data showing that M2 induces substantial amount of IL-10 in B cells and that pre-existing suppression of humoral immunity to Plasmodium by MHV68 in a primary infection also resulted in an ineffective memory responses upon challenge infec- tion. The rationale for the proposed work is that the development of new therapeutic strategies to en- sure protective humoral immunity develops in children depends on an understanding of the contributing factors that prevent the development of the humoral response in the first place. Guided by strong pre- liminary data, the central hypothesis will be tested by pursuing 3 specific aims: 1) To determine how the response of Tfh cells to an incoming Plasmodium infection is altered by M2-induced IL-10 secretion from MHV68-infected B cells 2) To determine how the breadth, affinity and longevity of the anti-malarial humoral response is altered by pre-existing gammaherpesvirus infection (3) To demonstrate that hu- moral immunity to P. falciparum in children is reduced by acute immunosuppressive EBV infection. The approach is innovative because our proposed research uses novel rodent models of EBV and Plasmo- dium co-infection and incorporates transcriptional profiling of B cell populations to enable the breadth of humoral immune responses to malaria to be determined. The proposed research is significant because it is expected to advance understanding of how the development of immunity to malaria can be ad- versely impacted by viral co-infections.

对疟疾的体液反应对于控制血期寄生虫血症和疟疾的广度至关重要。 抗体反应可以预防临床疟疾的发展。不明白为什么 一些儿童在早期未能对疟原虫感染产生足够的体液免疫反应 生活。恶性疟原虫疟疾和EB病毒（EBV）都是亚裔儿童感染的疾病。 撒哈拉非洲。大多数儿童在出生后的最初几年内就会出现 EB 病毒血清反应阳性， 通常无症状但伴有强效免疫抑制的事件。长期来看 该提案的目标是提供机械证据，证明急性伽马疱疹病毒重叠 感染负责抑制疟原虫感染期间体液免疫的发展。 儿童感染。使用完善的 EBV (MHV68) 和疟疾小鼠模型，目标是 该提案旨在确定 MHV68 la-如何改变对疟疾的体液免疫反应 张力相关蛋白 (M2)，并确定体液反应的哪些特征受到影响 （规模、广度、亲和力、寿命）。该提案的中心假设是归纳法 MHV68 感染的 B 细胞中 M2 产生的 IL-10 损害了滤泡辅助 T 细胞提供 B 细胞的能力 帮助产生针对传入疟原虫感染的有效、广谱抗体。这个假设—— sis 是根据我们已发表的初步数据制定的，表明 M2 会产生大量的 B 细胞中 IL-10 的量以及预先存在的对疟原虫体液免疫的抑制 原发感染中的 MHV68 也会导致攻击感染后的无效记忆反应。 。拟议工作的基本原理是开发新的治疗策略 儿童的保护性体液免疫的发展取决于对贡献因素的理解 首先阻碍体液反应发展的因素。在强大的预引导下 根据初步数据，将通过追求 3 个具体目标来检验中心假设：1）确定如何 M2 诱导的 IL-10 分泌改变了 Tfh 细胞对疟原虫感染的反应 来自 MHV68 感染的 B 细胞 2) 确定抗疟疾药物的广度、亲和力和寿命如何 体液反应因先前存在的伽马疱疹病毒感染而改变 (3) 证明 hu- 急性免疫抑制性 EBV 感染会降低儿童对恶性疟原虫的道德免疫力。这 方法是创新的，因为我们提出的研究使用了 EBV 和 Plasmo 的新型啮齿动物模型 dium 共感染并结合 B 细胞群的转录分析，以实现广泛的 对疟疾的体液免疫反应尚待确定。拟议的研究意义重大，因为 预计它将促进人们对疟疾免疫力的发展如何进行调整的理解。 病毒合并感染的严重影响。