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Rotavirus Outer Capsid Functions in Neutralization

轮状病毒外衣壳的中和功能

基本信息

批准号：
9808756
负责人：
Kristen M Ogden
金额：
$ 21.25万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-20 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808756
关键词：
Academic Medical Centers Amino Acid Sequence Animal Model Animals Antibodies Antibody Response Antigenic Diversity Antigens Attenuated Binding Biological Biological Assay Capsid Capsid Proteins Cell Line Cell model Cells Child Cultured Cells Data Developing Countries Development Diarrhea Dose Engineering Enterocytes Epidemic Epitopes Evolution Exhibits Foundations Genes Genetic Genome Genotype Geographic Locations Human Human Cell Line Immune response Immune system Immunize Immunologic Tests Immunologics In Vitro Individual Infant Infection Intestines Knowledge Laboratories Mediating Modeling Molecular Biology Molecular Vaccines Monkeys Morbidity - disease rate Oryctolagus cuniculus Outcome Pathogenicity Pattern Phenotype Plasmids Play Population Analysis Population Dynamics Proteins Publishing Reporting Research Resources Role Rotavirus Rotavirus Vaccines Rotavirus disease Serotyping Serum Specificity Specimen System Technology Testing Tropism Vaccinated Vaccination Vaccines Viral Virion Virus Work base burden of illness cell type diarrheal disease experimental study human model improved insight kidney cell kidney epithelial cell mortality neutralizing antibody population based pressure prevent programs protein function response reverse genetics uptake vaccine development vaccine efficacy vaccine evaluation vaccine response

项目摘要

PROJECT SUMMARY Rotavirus is an important cause of diarrheal morbidity and mortality in infants and children, particularly in developing countries. The rotavirus outer capsid is composed of VP4 and VP7 proteins, which facilitate viral attachment and entry and are primary targets of neutralizing antibodies. Rotaviruses exhibit narrow species and cell tropism, with human rotaviruses growing poorly in most cell lines and animal models. This phenotype, to which VP4 contributes significantly, has hampered studies of human rotavirus molecular biology and vaccine development. Following rotavirus vaccine introduction, there has been a significant decrease in severe rotavirus disease but concurrent emergence and spread of previously uncommon rotavirus serotypes and continued evolution of common serotypes. Differential patterns of circulating rotavirus serotypes that correlate with the specific vaccine implemented in a geographic region have been reported, suggesting vaccine- mediated serotype selection. While the antigenic diversity of contemporary and emerging human rotaviruses suggests antibodies elicited by current vaccines may neutralize them inequivalently, neutralization has not yet been empirically tested. The recent development of a plasmid-based reverse genetics system for a simian rotavirus and the use of human intestinal enteroids to culture human rotaviruses present new opportunities to elucidate outcomes of interactions between rotavirus outer-capsid antigens and vaccine-elicited antibodies. To test the hypothesis that that outer-capsid antigenic diversity, vaccine, and cell type influence serum neutralization of human rotaviruses, we propose two integrated Subaims. In Subaim 1, we will engineer chimeric simian rotaviruses incorporating outer-capsid genes from contemporary and emerging pathogenic human strains or vaccine strains using reverse genetics. We will quantify the capacity of serum antibodies elicited in rabbits or infants by different rotavirus vaccines to bind and neutralize the engineered viruses using standard assays, to permit comparison with previous studies. By isolating a human G or P type in an otherwise isogenic background, these studies will provide insight into antigen-specific functions of VP7 and VP4 in neutralization. In Subaim 2, we will perform replication and neutralization assays in human cell lines and human intestinal enteroids, using a panel of chimeric rotaviruses and differentially vaccinated rabbit and infant sera. These studies will provide biologically relevant insights into serum antibody responses elicited by different vaccines and roles of VP4 and VP7 in neutralization, which may support models that differ from those proposed based on animal rotaviruses or experiments in animal cell lines. Together, these studies will reveal individual rotavirus outer-capsid antigen functions in neutralization and differences in the breadth and specificity of vaccine-elicited serum antibody responses, provide insight into immunological pressures influencing rotavirus population dynamics, and enable development of improved rotavirus neutralization assays and platforms to test immune responses to current globally circulating rotaviruses.

项目总结