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ARS Home Midwest Area Ames, Iowa National Animal Disease Center Virus and Prion Research Research





- Nicholson, Eric
- Cassmann, Eric
- Greenlee, Justin
- Bian, Jifeng
- 2023
- 2022
- Publications
- Animal Health (103)

Research Project: Elucidating the Pathobiology and Transmission of Transmissible Spongiform Encephalopathies **Location:
                            Virus and Prion Research** 2022 Annual Report **Objectives**
                                

Objective 1: Develop highly sensitive detection tools to determine the distribution of CWD and scrapie prions in natural hosts (sheep, goats, cervids) and their environment.
Objective 2: Investigate the pathobiology of CWD, scrapie prion strains, and atypical TSEs in natural hosts including potential cross species transmission events.
Objective 3: Investigate the genetics of CWD susceptibility and resistance in white-tailed deer.
Objective 4: Evaluate the presence of and determine the appropriate methodology for CWD strain determination. **Approach**
                                

Eradication or control of a family of diseases is unlikely or impossible when an understanding of the basic mechanisms and influences on transmission are unknown and for which methods to evaluate disease status are lacking.
Scrapie and BSE represent the most thoroughly studied TSEs; however, significant knowledge gaps persist with regard to the atypical variants of these diseases. Further, much of the research emphasis to date on genetics of prion disease has focused on the recipient genotype rather than the source. Since both atypical BSE and atypical scrapie have been suggested to occur spontaneously, eradication of these diseases may not be possible unless we expand our understanding of the disease at both the source and recipient level. A better understanding of the tissue distribution and potential transmission of these atypical isolates is critical to understanding what risk these disease variants may pose to ongoing control and eradication efforts.
The European epizootic of BSE is waning and efforts to eradicate scrapie in the U.S. and abroad have progressed but are not complete. In the U.S., chronic wasting disease (CWD) presents the most serious challenge to regulatory efforts. CWD appears to be spreading unchecked in both free-ranging and farmed cervids. Methods for antemortem detection of TSEs in general and CWD in particular are needed to fulfill the goal of eradicating scrapie and controlling CWD. Performing these studies will allow us to address critical knowledge gaps that are relevant to developing measures to restrict further disease expansion beyond current, affected populations.
Understanding prion disease persistence in animal populations is challenging due to lack of tools for study and a less than complete understanding of transmission among animals within a flock or herd or in naturally occurring reservoirs. In addition to transmission between hosts of like species, free-ranging cervids may come in contact with numerous other species including cattle, sheep, and other susceptible hosts. Transmission of CWD to other species has been studied but limited with regard to the source genotype used.
The four primary objectives are inherently linked. Our focus is on developing tools needed for control and research, and using those tools to advance our understanding the complex disease process with the overall goal of eradication and control of disease in livestock, wildlife of economic importance, and potential wildlife reservoirs. **Progress Report**
                                

In work toward addressing Objective 1, Develop highly sensitive detection tools to determine the distribution of chronic wasting disease (CWD) and scrapie prions in natural hosts (sheep, goats, cervids) and their environment, we have worked closely with ARS researchers in Pullman, Washington, to develop a unified protocol for the detection of CWD prions by real-time quaking induced conversion (RT-QuIC) that utilizes an enrichment step that is capable of detection of disease in antemortem samples. We have also made significant progress on novel sampling procedures for detection of sheep scrapie that are not dependent on a veterinarian or trained veterinary technician as well as alternate choices of amyloid binding fluorescent dye. For Objective 2, Investigate the pathobiology of CWD, scrapie prion strains, and atypical TSEs in natural hosts including potential cross species transmission events, the studies in question have been initiated. Objective 3, Investigate the genetics of CWD susceptibility and resistance in white-tailed deer, consists of two subobjectives:  A) Investigate the susceptibility of white-tailed deer to CWD modeling direct contact exposure with infected deer, and B) Investigate the susceptibility of white-tailed deer to CWD after direct inoculation. The first of these has been initiated on schedule while the second has been delayed considerably (at least one or perhaps two years) due to insufficient animal space. Objective 4, Evaluate the presence of and determine the appropriate methodology for CWD strain determination, is dependent upon obtaining a diverse set of CWD isolates. We have begun, but not completed the acquisition of these samples. In summary, the goals of the project plan for FY22 consisted of 11 milestones, ten of which were either fully or substantially met. The one objective not met was due to insufficient animal availability and space constraints and will be initiated when those have been resolved. Briefly, NADC has BSL2 space for one study at a time and prion studies take years to complete. **Accomplishments**
                                

1. Two different naturally occurring isolates of chronic wasting disease differ in disease trajectory and biochemical properties. Misfolded prion protein is the causative agent of CWD, and the structure or conformation of the misfolded prion protein is inherently linked to the structure. There is limited knowledge about the variety and characteristics of isolates or strains of CWD that exist. A different isolate may have disease properties with important implications on disease transmission in wild and captive cervid herds. ARS scientists in Ames, Iowa, determined that there are two different isolates of chronic wasting disease (CWD) in captive herds of Rocky Mountain elk. In this study, they evaluated brain samples from two captive elk herds that had different prevalence and onset of disease. The differences could not be explained by differences in the genetic backgrounds of the animals. Brain stem (obex region) samples of several elk from each site were compared for pattern of CWD prion deposition in the brain and stability of CWD associated misfolded prion protein.  Both of which have been utilized in the past as indicators of different prion strains. The stability of the CWD prions from these animals was found to be different with regard to guanidine unfolding. These findings suggest the difference in disease prevalence and trajectory is a result of different CWD isolates between the two sites and suggest different disease spread may result from different CWD strains, an important consideration in disease management for captive cervid herds. 2. Passage through a new species alters chronic wasting disease transmission. Due to the human consumption of cervid meat products and intermingling of various livestock species with wild cervid populations, there is significant interest in characterizing the possible host range of CWD. ARS scientists in Ames, Iowa, demonstrated that passage of chronic wasting disease (CWD) prion (the CWD causative agent) through meadow voles results in increased attack rates and decreased incubation periods when vole passaged CWD prions were then experimentally inoculated into raccoons, which is a ubiquitous omnivore present throughout North America. Passage of the CWD agent from deer through meadow voles, a scavenger present in much of the range where CWD occurs, results in changes in the biological behavior of the CWD agent when that material is used to inoculate raccoons. This research is of interest to regulatory officials, or anyone interested in controlling CWD in wildlife or captive cervid herds. 3. Sheep accumulate abnormal prion protein in lymph nodes after oronasal exposure to chronic wasting disease prions. Several livestock species including sheep, deer, and elk are afflicted by prion diseases. In sheep the disease is called scrapie. In deer and elk, the disease is called chronic wasting disease (CWD). The source of CWD is unknown, but it is speculated that the origin of CWD may have been due to a species jump of scrapie in sheep to deer. Due to the human consumption of cervid meat products and intermingling of various livestock species with wild cervid populations, there is significant interest in characterizing the possible species that CWD may infect. This study reports preliminary results of an ongoing multi-year experiment on the oronasal transmission of CWD from white-tailed deer to sheep. After a five-year period ARS scientists in Ames, Iowa, determined that 1/7 sheep had detectable CWD prions in the tonsil and retropharyngeal lymph nodes (lymph nodes located near the throat that are routinely tested for CWD prions). Infectivity of these prions was confirmed using a bioassay with transgenic mice expressing cervid prion protein. These results demonstrate the susceptibility of sheep to the agent of CWD after a prolonged incubation period. Since the original experiment ended after five years, it is unknown if the sheep would have remained asymptomatic or developed clinical prion disease given a longer incubation period. It is also unknown if sheep are capable of shedding or transmitting CWD prions. Although these findings support the possibility of scrapie transmission to deer, additional research is necessary to further characterize the transmission properties of the CWD agent in sheep and other species. **Review Publications**
                            *Dassanayake, R.P., Atkinson, B.M., Mulls, A.S., Falkenberg, S.M., Nicholson, E.M., Casas, E., Narasimhan, B., Bearson, S.M. 2021. Bovine NK-lysin peptides exert potent antimicrobial activity against multidrug-resistant Salmonella outbreak isolates. Nature Scientific Reports. 11(1). Article 19276. https://doi.org/10.1038/s41598-021-98860-6.*
                                *Dassanayake, R.P., Porter, T.J., Samorodnitsky, D., Falkenberg, S.M., Nicholson, E.M., Tatum, F.M., Briggs, R.E., Palmer, M.V., Casas, E. 2022. Comparative study of antibacterial activity and stability of D-enantiomeric and L-enantiomeric bovine NK-lysin peptide NK2A. Biochemical and Biophysical Research Communications. 595:76-81. https://doi.org/10.1016/j.bbrc.2022.01.071.*
                                *Cassmann, E.D., Moore, S., Greenlee, J.J. 2021. Experimental oronasal transmission of chronic wasting disease agent from white-tailed deer to Suffolk sheep. Emerging Infectious Diseases. 27(12). https://doi.org/10.3201/eid2712.204978.*
                                *Martins, M., Boggiatto, P.M., Buckley, A., Cassmann, E.D., Falkenberg, S.M., Caserta, L.C., Fernandes, M.H., Kanipe, C.R., Lager, K.M., Palmer, M.V., Diel, D.G. 2022. From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in highly susceptible white-tailed deer. PLoS Pathogens. 18(3). Article e1010197. https://doi.org/10.1371/journal.ppat.1010197.*
                                *Lambert, Z., Greenlee, J.J., Cassmann, E.D., West Greenlee, H.M. 2021. Differential accumulation of misfolded prion strains in natural hosts of prion diseases. Viruses. 13(12). Article 2453. https://doi.org/10.3390/v13122453.*
                                *Moore, S., Carlson, C., Schneider, J., Johnson, C., Greenlee, J.J. 2022. Increased attack rates and decreased incubation periods in raccoons with chronic wasting disease passaged through meadow voles. Emerging Infectious Diseases. 28(4). Article 210271. https://doi.org/10.3201/eid2804.210271.*
                                *Wang, Z., Qin, K., Camacho, M., Ignazio, C., Yuan, J., Shen, P., Greenlee, J.J., Kong, Q., Mastrianni, J., Zou, W. 2021. Generation of human chronic wasting disease in transgenic mice. Acta Neuropathologica. 9. Article 158. https://doi.org/10.1186/s40478-021-01262-y.*
                                *Nichols, T.A., Nicholson, E.M., Liu, Y., Spraker, T.R., Wood, M., Lavelle, M., Fischer, J., Kong, Q., Vercauteren, K.C. 2021. Detection of two dissimilar Chronic Wasting Disease isolates in two captive Rocky Mountain elk (Cervus canadensis) herds. Prion. 15(1):207-215. https://doi.org/10.1080/19336896.2021.1982333.*
                                *Cassmann, E.D., Frese, A.J., Moore, S.J., Greenlee, J.J. 2022. Transmission of raccoon passaged chronic wasting disease agent to white-tailed deer. Viruses. 14(7). Article 1578. https://doi.org/10.3390/v14071578.*


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