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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

基本信息

批准号：
10080707
负责人：
Nathan Schmidt
金额：
$ 51.12万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-11 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080707
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 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 Parasitic infection 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 bacterial community fungus gut bacteria gut microbes gut microbiome gut microbiota imprint microbiota mortality mouse model novel novel therapeutics prevent programs translational approach translational study ward

项目摘要

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.

疟原虫属寄生虫的感染导致了2亿多疟疾病例，死亡人数更多

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence of Microbiome-Drug Interaction between the Antimalarial Lumefantrine and Gut Microbiota in Mice.

抗疟药物 Lumefantrine 与小鼠肠道微生物群之间微生物组-药物相互作用的证据。

DOI：
10.4269/ajtmh.20-0333
发表时间：
2020
期刊：
The American journal of tropical medicine and hygiene
影响因子：
0
作者：
Ippolito,MatthewM;Denny,JoshuaE;Nenortas,Elizabeth;Shapiro,TheresaA;Schmidt,NathanW
通讯作者：
Schmidt,NathanW

Mechanistic insights into the interaction between the host gut microbiome and malaria.

DOI：
10.1371/journal.ppat.1011665
发表时间：
2023-10
期刊：
PLoS pathogens
影响因子：
6.7
作者：
通讯作者：

The gut microbiome, immunity, and Plasmodium severity.

肠道微生物组，免疫力和疟原虫严重程度。

DOI：
10.1016/j.mib.2020.08.006
发表时间：
2020-12
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Waide ML;Schmidt NW
通讯作者：
Schmidt NW

Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility.

商业实验室小鼠肠道微生物群的时空变化影响实验的再现性。

DOI：
10.1186/s12915-020-00810-7
发表时间：
2020
期刊：
BMC biology
影响因子：
5.4
作者：
Mandal,RabindraK;Denny,JoshuaE;Waide,MorganL;Li,Qingsheng;Bhutiani,Neal;Anderson,CharlesD;Baby,BeccaV;Jala,VenkatakrishnaR;Egilmez,NejatK;Schmidt,NathanW
通讯作者：
Schmidt,NathanW