Role of the gut microbiota in shaping severity of malaria

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 每年有40多万人，其中大部分是感染恶性疟原虫的儿童 撒哈拉非洲。大多数疟原虫感染要么没有症状，要么只导致轻微疟疾。一小块 感染进展为严重疟疾的比例可能危及生命。到目前为止，东道主因素 目前尚不清楚患者易患严重疟疾，也无法确定风险。 预测从无症状感染到严重疟疾进展的因素。这些知识差距阻碍了 发现预防严重疟疾的新战略。利用多种疟原虫和 小鼠品系，我们最近发表了一项新的观察，小鼠具有明显的肠道细菌 社区在疟疾严重程度和感染后体液免疫反应方面表现出差异 带着疟原虫。对严重疟疾耐药的小鼠表现出T滤泡辅助细胞(TFH)和生发中心升高 约氏疟原虫感染后(GC)B细胞数量与加速抗体类型转换的比较 易受感染的小鼠。当被预测患有轻度疟疾的小鼠被用抗体治疗时， TFH-GC B细胞通讯，他们产生了高寄生虫负担，类似于发展为严重 疟疾。这些新的观察结果支持了这一应用的科学前提，并表明 微生物组对GC反应的调节可能是其发生的关键机制 严重的疟疾。这项建议的目的是确定免疫机制，通过这些机制 肠道微生物群决定对严重疟疾的易感性，并确定特定的微生物和代谢物 对这一结果负责。这些研究将推动疟疾发病机制领域在新的世纪取得新的进展 并可能导致控制严重疟疾的新的转化方法，这反过来又可以节省 每年有数十万人死于严重的疟疾。这项提议的核心假设是 是特定的微生物及其代谢产物调节GC反应以确定对重症的易感性 疟疾。我们的假设将通过以下具体目标进行检验：目标1.确定 肠道微生物区系对小鼠GC反应的调节作用。目的2.测定TFH细胞和GC B细胞 小鼠肠道微生物区系调控的内在途径。目标3.鉴定特定的肠道细菌及其 决定小鼠对严重疟疾的抵抗力或易感性的代谢物。

Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill more than 400,000 people annually, the majority of whom are Plasmodium falciparum-infected children in sub- Saharan Africa. Most Plasmodium infections are either asymptomatic or cause only mild malaria. A small proportion of infections progress to severe malaria that can be life threatening. To date, the host factors that predispose patients to developing severe malaria are not known, and it has not been possible to identify risk factors that predict progression from asymptomatic infection to severe malaria. These knowledge gaps hinder discovery of new strategies for the prevention of severe malaria. Using multiple Plasmodium species and mouse strains, we have recently published the novel observation that mice with distinct gut bacterial communities exhibit differences in the severity of malaria and humoral immune response following infection with Plasmodium. Mice resistant to severe malaria exhibit elevated T follicular helper (Tfh) and germinal center (GC) B cell numbers and accelerated antibody class switching following Plasmodium yoelii infection compared to susceptible mice. When mice predicated to develop mild malaria were treated with antibodies that disrupt Tfh-GC B cell communication, they developed high parasite burdens, similar to mice that develop severe malaria. These new observations support the scientific premise of this application and suggest that gut microbiome-mediated modulation of the GC reaction may be a critical mechanism underlying the development of severe malaria. The objective of this proposal is to determine the immunological mechanisms by which the gut microbiome determines susceptibility to severe malaria and identify the specific microbes and metabolites responsible for this outcome. These studies will move the field of malaria pathogenesis forward in new directions and may lead to new translational approaches to control severe malaria, which could, in turn, save the hundreds of thousands of lives lost to severe malaria each year. The central hypothesis of this proposal is that specific microbes and their metabolites modulate GC reactions to determine susceptibility to severe malaria. Our hypothesis will be tested through the following specific aims: Aim 1. Determine the dynamics of gut microbiota-mediated modulation of the GC reaction in mice. Aim 2. Determine the Tfh cell- and GC B cell- intrinsic pathways modulated by the gut microbiota in mice. Aim 3. Identify the specific gut bacteria and their metabolites that determine resistance or susceptibility to severe malaria in mice.