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Determinants of yellow fever pathogenesis in humans

人类黄热病发病机制的决定因素

基本信息

批准号：
10260510
负责人：
Adam Lee Bailey
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2020-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260510
关键词：
Achievement Adverse event Aedes Africa South of the Sahara Animal Model Animals Applications Grants Asia Award Basic Science Benign Biological Biological Assay Bite Blood Coagulation Disorders Blood Coagulation Factor Blood specimen CRISPR/Cas technology Cell Line Cells Central America Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coagulation Process Complement Consumption Culicidae Data Development Disasters Disease Disease Progression Doctor of Philosophy Environment Europe Event Funding Mechanisms Generations Genes Gold HRK gene Hemorrhage Hepatocyte Human Immune In Vitro Infection Infectious Diseases Research Integration Host Factors Interferons Knock-out Kupffer Cells Laboratories Laboratory Research Lead Leadership Life Cycle Stages Liver Macaca Mediating Modeling Molecular Mus Myeloid Cells Natural Resistance North America Oceania Organ Pathogenesis Pathology Patients Physicians Play Population Positioning Attribute Predisposition Primates Principal Investigator Process Production Public Health Public Speaking Research Research Personnel Resistance Risk Role Science Scientific Inquiry Scientist Southeastern Asia Specimen Statistical Data Interpretation Structure Study models System Testing Time Tissues Transgenic Mice Transplantation Tropism United States National Institutes of Health Universities Utah Viral Viral Hemorrhagic Fevers Virus Virus Diseases Virus Replication Work Writing Xenograft procedure Yellow Fever Yellow Fever Vaccine Yellow fever virus animal facility base career cell type combat genome-wide high reward high risk human pathogen improved insight large scale production liver injury mouse model neglect nonhuman primate novel professor programs skills success tenure track tool vector mosquito virology whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Yellow fever (YF) is a deadly disease transmitted by the bite of infected Aedes aegypti mosquitoes. Although an effective vaccine for YF was invented in the 1930s, it is not amenable to large-scale production and has a high rate of adverse events (including death). As a result, YF continues to kill approximately 30,000 people each year. Moreover, due to the re-emergence of Aedes mosquito vectors, substantial portions of Southeast Asia, Oceania, and even Europe and North America are at increasing risk for introduction of the YF virus (YFV), which would be a public health disaster. In humans, YF presents as a classic viral hemorrhagic fever (VHF), causing severe coagulation abnormalities (i.e. coagulopathy) and end-organ damage. This contrasts with what happens in mice, where YFV infection is largely benign and characterized by a distinct lack of coagulopathy/hemorrhagic features. The host factors that determine the development of VHF in YF in humans are unknown. This project aims to identify these factors at both cellular and molecular levels. Currently, VHF in YF is thought to be driven by the infection of hepatocytes. However, unpublished data collected from Brazilian YF patients suggests that hepatocyte destruction alone is insufficient to explain the coagulopathy observed in YF. Aim 1 will test the hypothesis that the infection of immune cells plays a major (and previously underappreciated) role in the development of VHF in YF. This Aim will utilize YFV infection of transgenic mice that have been engrafted with human hepatocytes or human immune cells – two cell populations that are thought to play a major role in the VHF disease process – allowing the study YFV infection of these cell populations in isolation in this otherwise YF-resistant host. A range of coagulation tests will be performed on infected mice to determine the mechanism by which coagulopathy develops during YFV infection. Blood samples drawn daily from YFV-infected macaques – the gold-standard animal model for studying VHF in YF – also will be analyzed, as this will be essential for determining the timing and causal relationships between key events such as clot formation, clotting factor depletion, and liver damage. In Aim 2, a CRISPR-Cas9 genome wide knock-out screen will be performed utilizing human and mouse, hepatocyte and Kupffer cell lines, to identify the factors that render humans (and primates) uniquely susceptible to YFV. The factors that restrict YFV replication in the murine host – hypothesized to be an interferon-stimulated gene (ISG) based on preliminary data – also will be identified. ‘Hits’ from this screen will be validated using targeted gene knock-out and trans-complementation in vitro. This will identify host factors that are essential in the YFV life cycle, and may lead to the generation of new YF-susceptible mouse models. This research will generate information and biological tools that can be used to combat YF specifically, and VHF more generally. This award will also help the principal investigator, Dr. Adam Bailey, MD, PhD, establish himself as an independent researcher and enable him to pursue high-reward projects that would otherwise not be feasible.

项目总结/文摘