Gut microbiota and human malaria

摘要 由疟原虫属寄生虫感染导致2亿多疟疾病例，并导致更多人死亡 每年超过40万人，其中大多数是撒哈拉以南地区感染恶性疟原虫的儿童 非洲。大多数恶性疟原虫感染是无症状的。虽然一些感染进展到临床 单纯疟疾(UM)，一小部分感染进展为临床形式的严重疟疾(例如， 严重疟疾贫血(SMA)、脑型疟疾(CM))，这些疾病导致与恶性疟原虫有关的死亡。 到目前为止，人们还不完全清楚哪些因素导致恶性疟原虫感染的易感性。 进展为临床UM或严重疟疾。肠道微生物区系为宿主提供了许多好处，包括 调节宿主免疫力。在小鼠模型系统中，我们最近发表了具有不同肠道的小鼠 细菌群落在疟疾的严重程度和感染后的体液免疫方面表现出差异。 具有特定细菌群落特征的小鼠在疟原虫感染后出现相对较低的寄生虫血症 约氏杆菌感染，表现为T滤泡辅助细胞(TFH)和生发中心(GC)B细胞数量增加 与具有不同细菌群落特征的小鼠相比，加速抗体类别的转换 出现了高度寄生虫血症。当出现低寄生虫血症的小鼠接受干扰抗体治疗时 在TFH-GC B细胞通讯中，它们的寄生虫负担与对照组小鼠相似。这些发现表明 微生物组对GC反应的调节可能是其发生的机制之一 严重的疟疾。目前，还没有关于肠道微生物群对人类健康影响的明确的人类数据。 恶性疟原虫感染向临床疟疾的进展。值得注意的是，我们的初步数据表明 无症状寄生虫血症(AP)感染的儿童的粪便细菌群落与儿童不同 用SMA对马里儿童的粪便细菌进行前瞻性分析，发现有显著差异 维持或控制AP感染的儿童与患发热性疟疾的儿童之间的差异。这些 新的发现支持这一中心假设，即人类肠道微生物区系的组成是一个危险因素 通过调节GC反应发展临床疟疾。我们的假设将通过 以下具体目标：目标1.证明人类肠道微生物群能够引起差异 易患疟疾。目的2.确定人体肠道微生物区系在调节GC反应中的作用 在感染疟原虫之后。

ABSTRACT Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill more than 400,000 people annually, most of whom are Plasmodium falciparum-infected children in sub-Saharan Africa. The majority of P. falciparum infections are asymptomatic. While some infections progress to clinical uncomplicated malaria (UM), a small percentage of infections progress to clinical forms of severe malaria (e.g., severe malarial anemia (SMA), cerebral malaria (CM)), which are responsible for P. falciparum related deaths. To date, it is not fully understood what factors contribute towards the susceptibility of P. falciparum infection progressing to clinical UM or severe malaria. Gut microbiota provide many benefits to the host, including modulation of host immunity. In a murine model system, we recently published that mice with distinct gut bacterial communities exhibit differences in the severity of malaria and humoral immunity following infection. Mice with a specific bacterial community profile developed relatively low parasitemia following Plasmodium yoelii infection and exhibited elevated T follicular helper (Tfh) and germinal center (GC) B cell numbers and accelerated antibody class switching compared to mice with a different bacterial community profile that developed high parasitemia. When mice that develop low parasitemia were treated with antibodies that disrupt Tfh-GC B cell communication, they had similarly high parasite burdens as control mice. These findings suggest that microbiome-mediated modulation of the GC reaction may be a mechanism underlying the development of severe malaria. Currently, there are no definitive human data on the effect of the gut microbiome on the progression of P. falciparum infection to clinical malaria. Of note, our preliminary data demonstrate that children with asymptomatic parasitemia (AP) infections have different stool bacteria communities than children with SMA, and prospective analysis of stool bacteria in Malian children has identified significant differences between children who maintain or control AP infection versus children who develop febrile malaria. These novel findings support the central hypothesis that the composition of gut microbiota in humans is a risk factor for developing clinical malaria through modulation of GC reactions. Our hypothesis will be tested through the following specific aims: Aim 1. Demonstrate the human gut microbiome is capable of causing differential susceptibility to malaria. Aim 2. Determine the role of human gut microbiota in modulating GC reactions following Plasmodium infection.