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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：
CHANDY C. JOHN
金额：
$ 74.15万
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：
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/10450781
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 Persons 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

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