Gut microbiota and human malaria
肠道微生物群和人类疟疾
基本信息
- 批准号:10450781
- 负责人:
- 金额:$ 74.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:16S ribosomal RNA sequencingAffectAfrica South of the SaharaAfricanAntibodiesB-LymphocytesBacteriaBiological ModelsCause of DeathCell CommunicationCell CountCerebral MalariaCessation of lifeCharacteristicsChildClinicalCommunicable DiseasesCommunitiesDataDevelopmentDiseaseEvolutionExhibitsFecesFeverFutureGerm-FreeHealthHumanHumoral ImmunitiesImmunityImmunoglobulin Class SwitchingInfectionKnowledgeLeadMalariaMalawiMaliMediatingMicrobeMusOutputParasitemiaParasitesParasitic infectionPersonsPhysiologyPlasmodiumPlasmodium falciparumPlasmodium yoeliiPredispositionPublishingReactionRiskRisk FactorsRodentRoleSamplingSeveritiesStructure of germinal center of lymph nodeTaxonomyTestingUgandabacterial communitycohortfollow-upgut bacteriagut microbiomegut microbiotahuman dataimprovedmalarial anemiamicrobiomemortalitymouse modelnovelpreventprospectiveresponsetranscriptome sequencingtranslational study
项目摘要
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.
摘要
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,其中大多数是撒哈拉以南非洲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
单纯性疟疾(UM),一小部分感染进展为严重疟疾的临床形式(例如,
严重的疟疾性贫血(SMA)、脑型疟疾(CM)),它们是恶性疟原虫相关死亡的原因。
迄今为止,尚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。肠道微生物群为宿主提供许多益处,包括
调节宿主免疫力。在一个小鼠模型系统中,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发生相对较低的寄生虫血症
约氏感染,并表现出升高的T滤泡辅助细胞(Tfh)和生殖中心(GC)B细胞数量,
与具有不同细菌群落特征的小鼠相比,
出现了高寄生虫血症当用抗体治疗低寄生虫血症的小鼠时,
Tfh-GC B细胞通讯,它们具有与对照小鼠相似的高寄生虫负荷。这些发现表明
微生物组介导的GC反应调节可能是导致
严重的疟疾目前,还没有关于肠道微生物组对肠道微生物的影响的确切的人类数据。
恶性疟原虫感染进展为临床疟疾。值得注意的是,我们的初步数据表明,
无症状寄生虫血症(AP)感染儿童的粪便细菌群落与儿童不同
与SMA,并在马里儿童粪便细菌的前瞻性分析已确定显着差异
保持或控制AP感染的儿童与发展为发热性疟疾的儿童之间的差异。这些
新的发现支持了一个核心假设,即人类肠道微生物群的组成是一个危险因素
用于通过调节GC反应开发临床疟疾。我们的假设将通过
具体目标:目标1。证明人类肠道微生物组能够导致差异
易患疟疾。目标2.确定人类肠道微生物群在调节GC反应中的作用
疟原虫感染后。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHANDY C. JOHN其他文献
CHANDY C. JOHN的其他文献
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{{ truncateString('CHANDY C. JOHN', 18)}}的其他基金
Neurodevelopmental outcomes in children with severe malaria
严重疟疾儿童的神经发育结果
- 批准号:
9040687 - 财政年份:2015
- 资助金额:
$ 74.15万 - 项目类别:
Neurodevelopmental outcomes in children with severe malaria
严重疟疾儿童的神经发育结果
- 批准号:
9196386 - 财政年份:2015
- 资助金额:
$ 74.15万 - 项目类别:
Northern/Pacific Universities Global Health Research Training Consortium
北部/太平洋大学全球健康研究培训联盟
- 批准号:
8356559 - 财政年份:2012
- 资助金额:
$ 74.15万 - 项目类别:
Northern/Pacific Universities Global Health Research Training Consortium
北部/太平洋大学全球健康研究培训联盟
- 批准号:
8710654 - 财政年份:2012
- 资助金额:
$ 74.15万 - 项目类别:
Northern/Pacific Universities Global Health Research Training Consortium
北部/太平洋大学全球健康研究培训联盟
- 批准号:
8672800 - 财政年份:2012
- 资助金额:
$ 74.15万 - 项目类别:
Northern/Pacific Universities Global Health Research Training Consortium
北部/太平洋大学全球健康研究培训联盟
- 批准号:
8779823 - 财政年份:2012
- 资助金额:
$ 74.15万 - 项目类别:
Northern/Pacific Universities Global Health Research Training Consortium
北部/太平洋大学全球健康研究培训联盟
- 批准号:
8877677 - 财政年份:2012
- 资助金额:
$ 74.15万 - 项目类别:
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