Suppression of anti-malarial humoral immune responses by gamaherpesviruses

对疟疾的体液反应在控制血期寄生虫血症和疟疾传播的广度方面是至关重要的。 抗体反应可防止临床疟疾的发展。不知道为什么 有些儿童在早期未能对疟原虫感染产生足够的体液免疫应答， 生活恶性疟原虫疟疾和爱泼斯坦巴尔病毒（EBV）都是亚热带地区的儿童感染。 撒哈拉非洲。大多数儿童在生命的最初几年内成为EBV血清阳性， 通常无症状但伴有强效免疫抑制的事件。长期 该提案的目标是提供机制证据，证明重叠的急性γ疱疹病毒会导致- 在疟原虫感染期间，感染是抑制体液免疫发展的原因。 儿童感染使用已建立的EBV（MHV 68）和疟疾的小鼠模型， 该提议是为了确定MHV 68 Ia如何改变对疟疾的体液免疫应答， 免疫相关蛋白（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）。这一建议的核心假设是， MHV 68感染的B细胞中M2对IL-10的作用损害了T滤泡辅助细胞提供B细胞的能力 有助于产生有效广谱抗体，以抵抗疟原虫感染。这个假托- SIS已经从我们发表的和初步的数据中公式化，表明M2诱导了大量的 B细胞中IL-10的量和预先存在的对疟原虫的体液免疫的抑制， 原发感染中的MHV 68在激发感染后也导致无效的记忆反应， 是的。拟议工作的理由是，新的治疗策略的发展，以EN- 当然，儿童保护性体液免疫的发展取决于对促进免疫的因素的理解。 这些因素首先阻止了体液反应的发展。以强有力的指导， 有限的数据，将通过追求3个具体目标来测试中心假设：1）为了确定如何 M2诱导的IL-10分泌改变了Tfh细胞对进入疟原虫感染的反应 2）为了确定抗疟药物的广度、亲和力和寿命如何影响MHV 68感染的B细胞， 预先存在的γ疱疹病毒感染改变了体液反应（3）为了证明hu- 急性免疫抑制性EBV感染降低了儿童对恶性疟原虫的道德免疫力。的 方法是创新的，因为我们提出的研究使用了新的EBV和Plasmo啮齿动物模型， dium共感染，并结合B细胞群的转录谱分析，以使广泛的 对疟疾的体液免疫反应有待确定。这项研究意义重大，因为 预计它将促进对疟疾免疫力发展的理解， 受病毒合并感染的影响。

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.