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Elucidating the immune response of Schreiber's bats to Lloviu virus infection in vitro and in vivo

阐明施赖伯蝙蝠对 Lloviu 病毒感染的体外和体内免疫反应

基本信息

批准号：
10458900
负责人：
Elke C Muhlberger
金额：
$ 24.38万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-24 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458900
关键词：
Animals Benign Biological Assay Blood Blood specimen Cell Culture Techniques Cell Line Cells Chiroptera Complex Country Data Deaminase Disease Disease Outbreaks Eastern Europe Ebola virus Enzymes Epidemic Europe Evolution Family Fatality rate Filovirus Fruit Gene Expression Genes Genetic Drift Genome Geography Goals Human Hungary Immune response In Vitro Infection Knock-in Knock-out Lead Light Marburgvirus Mediating Pathogenicity Pattern Play Population Procedures Process Public Health RNA RNA Editing RNA Viruses Recombinants Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Rousettus Sampling Serial Passage Southern Europe Spain System Viral Viral Genome Virus Virus Diseases Work Zoonoses adenosine deaminase apolipoprotein B mRNA editing enzyme base bat-borne comparative deep sequencing experimental study fitness genome editing in vivo insight member novel pandemic disease pathogenic virus polypeptide reverse genetics spillover event tool viral RNA viral fitness

项目摘要

ABSTRACT Bats play an important role as natural reservoirs of numerous RNA viruses with the potential to cause significant harm to humans. In this proposal, we focus on Lloviu virus (LLOV), an under-investigated filovirus that circulates in Schreiber’s bats (Miniopterus schreibersii) in Europe. Although the pathogenic potential of LLOV for humans is not known, the close relationship of LLOV to the highly pathogenic Ebola and Marburg viruses raises concerns that a potential spillover event could lead to an outbreak among humans. LLOV was first detected Schreiber’s bats in Spain in 2002 and then again in Hungary in 2016. Sequence comparison of the Spanish and the Hungarian LLOV RNA genomes suggests that RNA editing by cellular deaminases, such as ADAR and APOBEC, might play a role in LLOV sequence diversification. In this application, we propose to explore if host-mediated RNA editing drives LLOV sequence divergence and evolution in Schreiber’s bats. In Aim 1, we propose to sample Schreiber’s bats from geographically distinct colonies and obtain LLOV sequence information from infected bats for comparative analysis. We will further develop tools based on highly sensitive droplet RT-PCR and RNA FISH that allow to determine the expression pattern of ADARs and APOBECs in LLOV-infected bat cell culture and in blood samples from infected animals. In Aim 2, based on the determined ADAR and APOBEC expression patterns, we will knockout select ADAR and/or APOBEC genes that might be involved in LLOV RNA editing in the bat cell line and examine the role of these genes in LLOV sequence diversification and viral fitness in serial passaging experiments and cell culture infection studies. Upon completion of this work, we will have revealed whether host-specific RNA editors are the drivers of LLOV evolution in bat cells. This work will contribute to our understanding of host-driven viral sequence divergence and might help assess the risk of potential LLOV spillover events from bats to humans through host-driven changes in viral sequences.

摘要