Role of the gut microbiota in shaping severity of malaria

肠道微生物群在影响疟疾严重程度中的作用

• 批准号: 9307118
• 负责人: Nathan Schmidt
• 金额: $ 51.53万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-11 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307118
• 关键词: Adoptive Transfer; Affect; Africa South of the Sahara; Anemia; Antibodies; B-Lymphocytes; Bacteria; Biological Models; CD4 Positive T Lymphocytes; Cause of Death; Cell Communication; Cell Count; Cell physiology; Cerebral Malaria; Cessation of life; Child; Clinical; Communicable Diseases; Communities; Data; Development; Disease; Evolution; Exhibits; Foundations; Future; Germ-Free; Health; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Immunoglobulin Class Switching; Immunologics; Immunology; Inbreeding; Individual; Infection; Integration Host Factors; Knowledge; Lead; Life; Malaria; Mediating; Metabolic; Microbe; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Outcome; Parasite Control; Parasites; Pathogenesis; Pathology; Pathway interactions; Patients; Physiology; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Population; Predictive Factor; Predisposing Factor; Predisposition; Prevention strategy; Process; Publishing; Reaction; Resistance; Risk Factors; Rodent; Role; Severities; Shapes; Structure of germinal center of lymph node; Syndrome; Testing; Virus; Wild Type Mouse; fungus; gut microbiome; gut microbiota; imprint; killings; microbial community; microbiota; mortality; mouse model; novel; novel therapeutics; prevent; programs; translational approach; translational study; ward

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.

疟原虫属寄生虫感染导致2亿多例疟疾病例， 每年有40多万人，其中大多数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，要么只引起轻度疟疾。一个小 感染进展为严重疟疾的比例可能危及生命。迄今为止， 尚不清楚患者是否易患严重疟疾，也不可能确定风险 预测从无症状感染发展为严重疟疾的因素。这些知识差距阻碍了 发现预防严重疟疾的新战略。使用多种疟原虫， 我们最近发表了一项新的观察结果，即具有不同肠道细菌的小鼠 社区在疟疾的严重程度和感染后的体液免疫反应方面表现出差异 与疟原虫。对严重疟疾有抵抗力的小鼠表现出升高的T滤泡辅助细胞（Tfh）和生发中心 (GC)约氏疟原虫感染后B细胞数量和加速的抗体类别转换比较 对易感小鼠。当用抗体治疗被预测会发展为轻度疟疾的小鼠时， Tfh-GC B细胞通讯，它们产生了高寄生虫负荷，类似于小鼠， 疟疾这些新的观察结果支持了这一应用的科学前提，并表明肠道 微生物组介导的GC反应调节可能是发展的关键机制 严重的疟疾。这项建议的目的是确定免疫机制， 肠道微生物组决定了对严重疟疾的易感性，并确定了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的新进展， 方向，并可能导致新的转化方法来控制严重的疟疾，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 特定的微生物及其代谢物调节GC反应，以确定对严重 疟疾我们的假设将通过以下具体目标进行检验：目标1。确定的动态 肠道微生物群介导的小鼠GC反应调节。目标二。确定Tfh细胞和GC B细胞 由小鼠肠道微生物群调节的内在途径。目标3。确定特定的肠道细菌及其 这些代谢物决定了小鼠对严重疟疾的抵抗力或易感性。