Suppression of anti-malarial humoral immune responses by gamaherpesviruses

对疟疾的体液反应对于控制血期寄生虫病和疟疾的广度是至关重要的。 抗体反应对临床疟疾的发展具有保护作用。目前还不清楚为什么 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。恶性疟和爱泼斯坦-巴尔病毒(EBV)均为儿童亚型感染。 撒哈拉非洲。大多数儿童在出生后的头几年内EBV血清呈阳性， 通常无症状但伴有强烈的免疫抑制的事件。从长远来看 这项提案的目标是提供机械证据，证明重叠的急性伽马疱疹病毒硬币- 感染负责抑制疟原虫体内体液免疫的发展。 对儿童的感染。利用已建立的EBV(MHV68)和疟疾小鼠模型，目的是 这项建议是为了确定MHV68是如何改变疟疾的体液免疫反应的-- 短暂性相关蛋白(M2)，并确定体液反应的哪些特征受到影响 (规模、广度、亲和力和寿命)。这一提议的中心假设是，归纳 MHV68感染的B细胞M2表达IL-10影响T滤泡辅助细胞提供B细胞的能力 有助于针对即将到来的疟原虫感染产生有效的广谱抗体。这个假说- SIS是从我们公布的初步数据中得出的，这些数据表明，M2导致了大量的 白介素10在B细胞中的含量及其对疟原虫体液免疫的抑制作用 MHV68在初次感染时也导致对挑战信息的无效记忆反应。 提顿。这项拟议工作的基本原理是，开发新的治疗策略以增强- 儿童保护性体液免疫的形成取决于对体液免疫因素的理解 首先，阻碍体液反应发展的因素。在强大的预制力的指引下 有限的数据，中心假设将通过追求3个具体目标来检验：1)确定 M2诱导的IL-10分泌改变TFH细胞对传入疟原虫感染的反应 从MHV68感染的B细胞2)确定如何广度、亲和力和长寿的抗疟疾 体液反应被预先存在的伽马疱疹病毒感染所改变(3)，以证明人-人-疱疹病毒。 儿童对恶性疟原虫的道德免疫力因急性免疫抑制EBV感染而降低。这个 方法是创新的，因为我们提出的研究使用了EBV和血浆的新型啮齿动物模型- 并结合了B细胞群体的转录图谱，以使广泛的 对疟疾的体液免疫反应有待确定。这项拟议的研究具有重要意义，因为 预计这将促进人们对如何发展对疟疾的免疫的理解。 受到病毒混合感染的严重影响。

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.