Gut microbiota and human malaria

肠道微生物群和人类疟疾

• 批准号: 10058405
• 负责人: CHANDY C. JOHN
• 金额: $ 71.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10058405
• 关键词: 16S ribosomal RNA sequencing; Affect; Africa South of the Sahara; African; Antibodies; B-Lymphocytes; Bacteria; Biological Models; Cause of Death; Cell Communication; Cell Count; Cerebral Malaria; Cessation of life; Characteristics; Child; Clinical; Communicable Diseases; Communities; Data; Development; Disease; Evolution; Exhibits; Feces; Fever; Future; Germ-Free; Health; Human; Humoral Immunities; Immunity; Immunoglobulin Class Switching; Infection; Knowledge; Lead; Malaria; Malawi; Mali; Mediating; Microbe; Mus; Output; Parasitemia; Parasites; Parasitic infection; Physiology; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Predisposition; Publishing; Reaction; Risk; Risk Factors; Rodent; Role; Sampling; Severities; Structure of germinal center of lymph node; Taxonomy; Testing; Uganda; bacterial community; cohort; follow-up; gut bacteria; gut microbiome; gut microbiota; human data; improved; malarial anemia; microbiome; mortality; mouse model; novel; prevent; prospective; response; transcriptome sequencing; translational study

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.

抽象的 寄生虫感染质子属会导致超过2亿例疟疾病例并杀死更多 每年超过40万人，其中大多数是萨哈拉以下的疟原虫感染的儿童 非洲。大多数恶性疟原虫感染无症状。虽然某些感染发展为临床 简单的疟疾（UM），一小部分感染发展为严重疟疾的临床形式（例如， 严重的疟疾贫血（SMA），脑疟疾（cm），导致恶性疟原虫相关的死亡。 迄今为止，尚不完全了解哪些因素有助于恶性疟原虫感染的易感性 发展为临床或严重疟疾。肠道微生物群为主机提供许多好处，包括 宿主免疫的调节。在鼠模型系统中，我们最近发表了具有独特肠道的小鼠 细菌群落在感染后表现出疟疾的严重程度和体液免疫力的差异。 具有特定细菌群体特征的小鼠在疟原虫后出现相对较低的寄生虫血症 YOELII感染，表现出升高的T卵泡辅助器（TFH）和生发中心（GC）B细胞数量和 与具有不同细菌社区概况的小鼠相比，加速抗体类转换 发展高寄生虫血症。当患有低寄生虫血症的小鼠用破坏的抗体治疗 TFH-GC B细胞通信，它们像对照小鼠一样具有同样的高寄生虫负担。这些发现表明 微生物组介导的GC反应调节可能是一种基础的机制 严重的疟疾。当前，尚无关于肠道微生物组影响的确切人类数据 恶性疟原虫感染到临床疟疾的进展。值得注意的是，我们的初步数据表明 无症状寄生虫病（AP）感染的儿童的粪便细菌群落与儿童不同 通过SMA和对马里儿童的粪便细菌的前瞻性分析已确定明显的差异 在维持或控制AP感染的儿童与发展高热疟疾的儿童之间。这些 新发现支持的中心假设是，肠道菌群在人类中是危险因素 通过调节GC反应来发展临床疟疾。我们的假设将通过 以下特定目的：目标1。证明人肠道微生物组能够引起差异 对疟疾的敏感性。 AIM 2。确定人类肠道菌群在调节GC反应中的作用 疟原虫感染后。