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和广度至关重要 抗体反应可抵抗临床疟疾的发展。不明白为什么 一些儿童未能在早期对疟原虫感染产生足够的体液免疫反应 生活。恶性疟原虫疟疾和爱泼斯坦巴尔病毒（EBV）都是亚下儿童感染 撒哈拉非洲。大多数儿童在生命的头几年内对EBV的血清反应阳性，这是 通常无症状的事件，但伴随着有效的免疫抑制。长期 该提案的目标是提供机械证据，表明急性伽马病毒硬币重叠 曲线负责抑制疟原虫内体液免疫发展的发展 儿童的饮食。使用良好的EBV的鼠标模型（MHV68）和疟疾的目的 该建议是确定MHV68 LA-的体液免疫反应如何改变 紧密相关的蛋白质（M2），并确定体液反应的哪些特征受到影响 （大小，广度，亲和力和寿命）。该提议的中心假设是归纳 在MHV68感染的B细胞中，M2的IL-10损害T卵泡辅助细胞提供B细胞的能力 帮助有效的广谱抗体产生传入的疟原虫感染。这个假设 SIS是根据我们发布的和初步数据提出的，表明M2诱导了大量 B细胞中IL-10的量以及预先存在对疟原虫的体液免疫的抑制 原发性感染中的MHV68还导致挑战不良的记忆反应无效。 tion。拟议工作的理由是制定新的治疗策略以纳入 确保儿童的保护性体液免疫力取决于对贡献的理解 首先阻止体液反应发展的因素。在强大的前指导 限量数据，中心假设将通过追求3个具体目的来检验：1）确定如何确定如何 M2诱导的IL-10分泌改变了TFH细胞对传入疟原虫感染的反应 从MHV68感染的B细胞2）确定抗疟疾的宽度，亲和力和寿命如何 预先存在的γ掌病毒感染（3）可以改变体液反应（3） 急性免疫抑制EBV感染可降低对儿童恶性疟原虫的道德免疫。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共感染并结合了B细胞群体的转录分析，以实现 对要确定疟疾的体液免疫反应。拟议的研究很重要，因为 预计将进一步了解疟疾免疫的发展如何。 受病毒共感染的影响。