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Redefining the zoonotic potential of chronic wasting disease

重新定义慢性消耗性疾病的人畜共患潜力

基本信息

批准号：
10610969
负责人：
Sabine Gilch
金额：
$ 27万
依托单位：
UNIVERSITY OF CALGARY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610969
关键词：
Address American Animals Asia Astrocytosis Biochemical Biological Bovine Spongiform Encephalopathy Brain Cattle Cell Culture Techniques Characteristics Chronic Wasting Disease Clinical Consumption Data Deer Deposition Disease Disease Outbreaks Dissociation Eating Endopeptidase K Europe Euthanasia Exhibits Exposure to Farm Feces Goals Health Human In Vitro Incubated Infection Link Macaca Macaca fascicularis Microtus Modeling Molecular Mus Neurodegenerative Disorders North America Oral Pathologic Pathway interactions Peptide Hydrolases Persons Phenotype PrP PrPSc Proteins Prion Diseases Prions Process Property Protein Fragment Protein Isoforms Public Health Reindeer Research Resistance Risk Rodent Route Saliva Testing Time Tissues Toxic effect Transgenic Mice Urine Zoonoses brain cell cervid disease transmission driving force epidemiologic data experimental study human model humanized mouse in vivo innovation insight mouse model nonhuman primate overexpression prion seeds reconstitution response single-cell RNA sequencing transmission process

项目摘要

The rapid expansion of chronic wasting disease (CWD), a prion disease of free-ranging and farmed deer, elk and moose, is a major and ongoing threat in North America. Approximately 1 in 36 Americans hunt deer and elk and eat venison, and it is estimated that 7,000 – 15,000 CWD-infected cervids are consumed annually. This fuels growing concerns about the human health risks imposed by CWD. There are no documented cases of CWD transmission to humans, even though with the long incubation periods of all prion diseases and the unknown presentation of CWD in humans definite conclusions are not possible. The zoonotic potential of prion diseases has been exemplified by bovine spongiform encephalopathy (BSE, mad cow disease) which resulted in a new form of human prion disease (vCJD). BSE was transmissible to Cynomolgus macaques and transgenic mice expressing the human prion protein. Initial results of CWD transmission studies to the same non-human primate and mouse models of human prion disease were not successful, corroborating the conclusion that the zoonotic potential of CWD is low, if not absent. Our groups were part of a consortium that inoculated Cynomolgus macaques via different routes with CWD. Some animals exhibited subtle clinical signs reminiscent of prion disease, and upon euthanasia, weak signs of vacuolation, PrPSc deposition and astrocytosis in the brain were found, while no proteinase K (PK) resistant prion protein (PrP) was detectable. We have now demonstrated for the first time that CWD from macaques can transmit clinical prion disease to transgenic mouse models of CWD and human prion disease, albeit in the absence of detectable PK-resistant PrP. Bona fide PrPSc was only detected upon 3rd passage from mouse to bank vole models. Altogether, this is the first evidence that CWD very likely has zoonotic potential. The goal of the current proposal is to redefine the zoonotic potential of CWD by characterizing the biological properties of CWD prions emerging upon experimental transmission into macaques, for obtaining important information on how CWD could manifest in humans. In Aim 1, we will study whether CWD from macaque (CWDmac) in bank voles represents a new prion strain, by comparing biochemical and biological properties to an array of known prion strains from different species. Aim 2 addresses the question whether CWDmac represents an intermediate prion strain, adaptable to cervids or humans upon passage, and possessing an expanded host range. We will address this by in vivo passage in cervidized or humanized mouse models. In vitro, we will utilize serial PMCA and a newly generated PrP0/0 cell culture model for infection, upon reconstitution with PrP from different species. In Aim 3, we will shed light on the observed dissociation between infectivity and the presence of bona fide PrPSc. We propose to identify atypical PrP fragments associated with CWDmac, and we will elucidate brain cell responses to CWDmac exposure by innovative single cell RNA sequencing. In summary, our studies will uncover the possible manifestation of CWD in humans, which is of critical importance for drawing definite conclusions about the zoonotic potential of CWD.

慢性消耗性疾病（CWD）是自由放养和养殖鹿、麋鹿的一种朊病毒疾病