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Journal of Veterinary Diagnostic Investigation Vol. 18 Issue 6, 553-557
Copyright © 2006 by the American Association of Veterinary Laboratory Diagnosticians
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Detection of PrPCWD in postmortem rectal lymphoid tissues in Rocky mountain elk (Cervus elaphus nelsoni) infected with chronic wasting disease

Terry R. Spraker1, Thomas L. Gidlewski, Aru Balachandran, Kurt C. VerCauteren, Lynn Creekmore and Randy D. Munger

Correspondence: 1Corresponding Author: Terry R Spraker, Colorado State University Diagnostic Laboratory, Colorado State University, 300 W Drake Rd, Fort Collins, CO 80526, e-mail: Terry.Spraker{at}colostate.edu


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Preclinical diagnostic tests for transmissible spongiform encephalopathies have been described for mule deer (Odocoileus hemionus), using biopsy tissues of palatine tonsil, and for sheep, using lymphoid tissues from palatine tonsil, third eyelid, and rectal mucosa. The utility of examining the rectal mucosal lymphoid tissues to detect chronic wasting disease (CWD) was investigated in Rocky Mountain elk (Cervus elaphus nelsoni), a species for which there is not a live-animal diagnostic test. Postmortem rectal mucosal sections were examined from 308 elk from two privately owned herds that were depopulated. The results of the postmortem rectal mucosal sections were compared to immunohistochemical staining of the brainstem, retropharyngeal lymph nodes, and palatine tonsil. Seven elk were found positive using the brainstem (dorsal motor nucleus of the vagus nerve), retropharyngeal lymph nodes, and palatine tonsil. Six of these elk were also found positive using postmortem rectal mucosal sections. The remaining 301 elk in which CWD-associated abnormal isoform of the prion protein (PrPCWD) was not detected in the brainstem and cranial lymphoid tissues were also found to be free of PrPCWD when postmortem rectal mucosal sections were examined. The use of rectal mucosal lymphoid tissues may be suitable for a live-animal diagnostic test as part of an integrated management strategy to limit CWD in elk.

Key Words: Chronic wasting disease • rectal lymphoid tissues • Rocky Mountain elk


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Chronic wasting disease (CWD), a transmissible spongiform encephalopathy, has been reported in captive and free-ranging mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni).10,11,13,17–19 Chronic wasting disease has been devastating in the captive elk industry. An estimated 12,000 to 14,000 captive elk have been killed in the western United States and western Canada in the past 5–6 years to control the disease. Several thousand free-ranging mule deer, white-tailed deer, and elk have also been killed in attempts to limit the spread of the disease in the wild. Captive elk and deer cannot be ruled out as sources of CWD for free-ranging and ranch-raised cervids; therefore, eradication of CWD in captive herds is a critical component of any strategy to control CWD. An accurate diagnostic test to identify infected elk during early preclinical stages of disease is essential for the success of this program. The objective of this study was to compare the accuracy of detecting the CWD-associated abnormal isoform of the prion protein (PrPCWD) in postmortem rectal lymphoid tissue sections compared with in the brainstem, retropharyngeal lymph nodes, and palatine tonsils in Rocky Mountain elk.


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A captive herd of 297 elk that had a single case of CWD 1 year previously was depopulated. Eleven elk from a small herd that was thought to be free of CWD were also killed and examined. The 308 total elk examined included 182 cows, 64 calves, and 62 bulls. Ages for the animals were recorded. The heads of these elk were brought to the Colorado State University Diagnostic Laboratory for CWD testing. The brainstem, retropharyngeal lymph nodes, and palatine tonsils were collected from each elk and immersed in 10% neutral buffered formalin. At the same time the heads were removed, the terminal 8–10 cm of rectum was also collected from each elk and taken to the Colorado State University Diagnostic Laboratory. A 1.0- to 1.5-cm strip of mucosa was removed approximately 0.5- to 1.0-cm anterior to the mucocutaneous junction of the anus from each sample. This strip of mucosa was immersed in 10% neutral formalin.

Preserved tissues from each elk were trimmed and embedded in three paraffin blocks. The first cassette contained a cross section of obex containing the dorsal motor nucleus of the vagus nerve. The second cassette contained a single section from each of the retropharyngeal lymph nodes and one section of palatine tonsil. The third cassette contained multiple cross sections of the strip of rectal mucosa. Blocks were sectioned at 5 µm, and tissue ribbons were mounted on positively charged glass slidesa and dried in a 65°C oven overnight. Slides were deparaffinized, placed in 99% formic acida for 5 minutes at room temperature, and rinsed in running tap water for 5 minutes. Slides were then autoclaved for 20 minutes at 121°C in citrated buffer (pH 6.1),b cooled, and transferred into tromethamine (TRIS) buffer (APK Wash solution).c Staining was done with a NexES automated immunostainer at 37°C using the Basic Alkaline Phosphatase Red with Amplification Kit.c The primary antibody used (Anti-Prion 99)c was incubated for 32 minutes at 37°C. Only Amplifier A (37°C for 8 minutes) was used for staining, and Amplifier B was run using an empty dispenser. Slides were counterstained with hematoxylin.12 A positive control slide containing brain and lymphoid tissue was stained with each run of 19 test slides. This antibody recognizes transmissible spongiform encephalopathy–positive brain in cervids, ovines, and bovines after antigen retrieval and treatment with formic acid.12 This abnormal isoform of the prion protein has been associated with CWD of captive and free-ranging mule deer, white-tailed deer, and Rocky Mountain elk.5,7,12–14

A single section of brainstem at the level of the dorsal motor nucleus of the vagus nerve was scored according to the distribution of positive immunohistochemical staining (IHC).10,14 A grade of 1 (+) was characterized by the accumulation of PrPCWD in the lower half of the dorsal motor nucleus of the vagus nerve but no PrPCWD in the dorsal half of the nucleus or in any of the adjacent nuclei in this single section. A grade of 2 (++) was characterized by PrPCWD filling the dorsal motor nucleus of the vagus nerve but no PrPCWD in any of the adjacent nuclei. A grade of 3 (+++) was characterized by PrPCWD filling the dorsal motor nucleus of the vagus nerve and starting to accumulate in the adjacent nuclei. A grade of 4 (++++) was characterized by PrPCWD filling the dorsal motor nucleus of the vagus nerve and an abundance of PrPCWD accumulating within adjacent nuclei.

The appearance of a positive rectal mucosal lymphoid follicle was characterized by coarse, bright red, granular material within the follicle (Fig. 1). Lymphoid follicles free of IHC staining had a pale blue background (Fig. 2). Lymphoid nodes and palatine tonsils were graded on a scale of plus 1 (+) to plus 4 (++++). A plus one (+) was characterized by <10% of the follicles containing PrPCWD. A plus 2 (++) was characterized by >10% but <30% of the follicles containing PrPCWD. A plus 3 (+++) was characterized by >30% to <50% of the follicles containing PrPCWD. A plus 4 (++++) was characterized by >50% the follicles containing PrPCWD.


Figure 18060501
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  		Figure 1 Photomicrograph of 2 lymphoid follicles in an elk with chronic wasting disease. Immunohistochemical staining: Streptavidin-alkaline phosphatase method. Hematoxylin/bluing counterstain. Bar = 100 µm.

 

Figure 18060502
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  		Figure 2 Photomicrograph of a lymphoid follicle in an elk free of the CWD-associated abnormal isoform of the prion protein. Immunohistochemical staining: Streptavidin-alkaline phosphatase method. Hematoxylin/bluing counterstain. Bar = 200 µm.

 
Follicle number and age data were analyzed to determine the relationship of the number of rectal mucosa lymphoid follicles to animal age. The pathologist designated the tissue sections as acceptable or poor. Poor biopsies meant that tissues were torn, which made an accurate count of follicles difficult. The "poor" designation did not mean there were no follicles in the tissue sections.

Animals were grouped in the following age categories: 0.5 years (calf), 1.5 years (yearling), 2.5 years, 3.5 years, 4.5 years and ≥ 5.5 years, and a mean number of follicles per age category was calculated. A linear regression was performed on log-transformed follicle numbers by age category to confirm the association noted by gross observation of the means.


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A total of 308 elk were examined in this investigation. Of these elk, 7 had detectable PrPCWD in the dorsal motor nucleus of the vagus nerve, retropharyngeal lymph nodes, and palatine tonsil as revealed using IHC staining. None of these 7 elk showed any clinical signs of CWD before euthanasia. Six of the elk had detectable PrPCWD within follicles of the rectal mucosa (Table 1).


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  		Table 1 Summary of age, sex, and immunohistochemical staining of the brainstem, retropharyngeal nodes, and palatine tonsil compared to postmortem rectal lymphoid tissues in the 7 elk positive for the CWD-associated abnormal isoform of the prion protein.

 
The first elk that was positive for PrPCWD was a 2.5-year-old cow. Use of IHC detected PrPCWD in the dorsal motor nucleus of the vagus nerve of the brainstem, sections from both retropharyngeal lymph nodes, and a single section of palatine tonsil. The IHC section of brainstem was scored as a grade 2. On a routine hematoxylin and eosin (HE)–stained section, spongiform degeneration was not observed in the dorsal motor nucleus of the vagus nerve or in any of the adjacent nuclei. Two slides of rectal mucosa were examined: 167 follicles were found and 122 (73%) contained detectable PrPCWD.

The second elk that was positive for PrPCWD was a 7.5-year-old cow. Using IHC, PrPCWD was detected in the brainstem, sections from both retropharyngeal lymph nodes, and a single section of tonsil. The IHC section of brainstem was scored as a grade 3. On a routine HE-stained section, spongiform degeneration was observed in the dorsal motor nucleus of the vagus nerve but not in any of the adjacent nuclei. Two slides were examined from the rectal mucosa: 29 follicles were found and 20 (69%) contained detectable PrPCWD.

The third elk that was positive for PrPCWD was a 2.5-year-old cow. PrPCWD was detected in the brainstem, sections from both retropharyngeal lymph nodes, and a single section of tonsil. The IHC section of brainstem was scored as a grade 2. On a routine HE-stained section, spongiform degeneration was not observed in the dorsal motor nucleus of the vagus nerve or in any of the adjacent nuclei. One slide was examined from the rectal mucosa: 163 follicles were found and 85 (52%) contained detectable PrPCWD.

The fourth elk that was positive for PrPCWD was a 2.5-year-old cow. IHC documented PrPCWD in the brainstem, sections from both retropharyngeal lymph nodes, and a single section of tonsil. The IHC section of brainstem was scored as a grade 3. On a routine HE-stained section, spongiform degeneration was observed in the dorsal motor nucleus of the vagus nucleus but not in any of the adjacent nuclei. One slide was examined from the rectal mucosa: 10 follicles were found and 8 (80%) contained detectable PrPCWD.

The fifth elk that was positive for PrPCWD was a 1.5-year-old bull. Use of IHC demonstrated PrPCWD in the brainstem, sections from both retropharyngeal lymph nodes, and a single section from the tonsil. The IHC section of brainstem was scored as a grade 3. On a routine HE-stained section, spongiform degeneration was observed in the dorsal motor nucleus of the vagus nerve but not in any of the adjacent nuclei. One slide was examined from the rectal mucosa: 90 follicles were found and 56 (62%) contained detectable PrPCWD.

The sixth elk that was positive for PrPCWD was a 6.5-year-old bull. IHC documented PrPCWD in the brainstem, sections from both retropharyngeal lymph nodes, and a single section from the tonsil. The IHC section of brainstem was scored as a grade 3. On a routine HE-stained section, spongiform degeneration was observed in the dorsal motor nucleus of the vagus nerve but not in any of the adjacent nuclei. One slide was examined from the rectal mucosa: 12 follicles were found and 6 (50%) contained detectable PrPCWD.

The seventh elk that was positive for PrPCWD was a 4.5-year-old bull. PrPCWD was observed in the brainstem, sections from both retropharyngeal lymph nodes, and a single section of tonsil. The IHC section of brainstem was scored as a grade 1, having only several neurons surrounded by a minimal accumulation of PrPCWD in each side of the dorsal motor nucleus of the vagus nerve; PrPCWD was not found in any of the adjacent nuclei of the brainstem. On a routine HE-stained section, spongiform degeneration was not observed in the dorsal motor nucleus of the vagus nerve or in any of the adjacent nuclei. Three slides of the postmortem rectal mucosal tissues were examined from this elk: 45 follicles were found and all were free of detectable PrPCWD.

A single slide of postmortem rectal mucosa from each of the remaining elk in which PrPCWD was not detected in the brainstem or cranial lymphoid tissues was examined for evidence of accumulation of PrPCWD. Rectal lymphoid follicles were found in 300 of these 301 elk, but PrPCWD was not detected in the rectal lymphoid follicles in any of these animals.

Of the 308 slides of rectal mucosa obtained, the pathologist described 15 as poor tissue sections, and they were not used in the analysis. The rectal tissue sections from the remaining 293 animals were grouped by age category and the mean number of rectal mucosal lymphoid follicles was calculated. The mean number of rectal mucosal lymphoid follicles decreased with each age category indicating a possible association between follicle numbers and animal age (Table 2). A significant linear regression relationship was demonstrated between age category and number of follicles (P≤0.0001) confirming this relationship.


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  		Table 2 The mean number of lymphoid follicles found in postmortem sections of rectal mucosa in specific age groups from 292 farm-raised Rocky Mountain elk.

 

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Early accumulation of PrPCWD in tonsil and retropharyngeal lymph nodes is a reliable marker for preclinical postmortem4,5,10–14 and antemortem16 diagnosis of CWD in deer. Experimental oral infection of mule deer resulted in PrPCWD accumulation in alimentary tract–associated lymphoid tissues (retropharyngeal lymph node, tonsil, Peyer's patches, mesenteric and ileoceocolic lymph nodes) as early as 42 days after infection.9

Preclinical and antemortem diagnosis of scrapie has been described in domestic sheep and is performed by biopsy of lymphoid tissue from tonsil,8,15 nictitating membrane,6 and rectal mucosa.1–3 The disease-associated isoform of the ovine prion protein is detectable in lymphoid tissue at approximately one-third to one-half of the incubation period in sheep, with the notable exception of sheep with the prion protein genotype VRQ/ARR, in which accumulation is limited to the central nervous system.8 This restricted distribution is also observed in a small percentage of sheep with other susceptible genotypes (O'Rourke, personal communication, January 10, 2006).

The pathogenesis of CWD in elk is less well defined. PrPCWD was detected in brain and retropharyngeal lymph nodes (68%), nodes only (19%), and brain only (13%) in a sample of 226 naturally infected farmed elk.10 If PrPCWD accumulates in the rectal mucosal lymphoid tissue at a frequency similar to that in the retropharyngeal lymph node, the relatively high percentage of CWD-infected elk with PrPCWD restricted to the central nervous system will limit the sensitivity of a preclinical test for diagnosing individual animals.

Another finding that would limit the use of this rectal mucosal test to identify individual animals in a herd is the results found in case 7. This 4.5-year-old bull was in an extremely early stage of CWD, having PrPCWD in lymphoid tissues of the head, but only a scant accumulation of PrPCWD around several neurons in the dorsal motor nucleus of the vagus nerve. Using only the rectal mucosal sections, this PrPCWD-positive elk would have been missed. The reason for the absence of PrPCWD in the rectal lymphoid tissues was not determined, but it may suggest that lymphoid tissues of the head may become infected before lymphoid tissues in the lower gut.

Another potential limitation to this technique is the reduction in number of follicles as individual elk age. In this preliminary study, numerous lymphoid follicles were found in the rectal mucosa in elk <5 years old, but fewer follicles were found in elk >5 years old. However, the follicle number was adequate to diagnose CWD in 6 of 7 elk ages ranging from 1.5 to 8.5 years. It has been suggested that a minimum of 6 follicles should be evaluated in sheep eyelids to test scrapie.6 The mean number of lymphoid follicles in the >5-year-old age group was 13, suggesting even this group could yield enough follicles for evaluation.

Even though this technique has some limitations, identifying infected herds by entire-herd screening may be a useful adjunct to the CWD control program by identifying positive elk before clinical signs can be detected. In this study of 308 elk, the postmortem rectal mucosal tissue sections did identify 6 of 7 (86%) positive elk with a single test. If this procedure is performed in a herd once a year for several years, it may prove to be beneficial by identifying nonclinical CWD-positive animals, which can then be culled. This technique may also be useful for assessing the level of infection in a given herd. Perhaps these management strategies may result in limiting the spread of CWD in affected herds. This technique may have value in other uses, such as in experimental studies of CWD pathogenesis and transmission.


   Acknowledgments
 
We would like to thank Wayne Cunningham and the numerous state and federal personnel for euthanizing the elk and collecting the brainstem, retropharyngeal lymph nodes, and palatine tonsils. We would especially like to thank Keith Roehr, Richanne Lomkin, and John Maulsby for collecting the rectums from these elk. We would like to thank Bridget Schuler, Cecily Powers, Jenny Powers, Vicki Jameson, Scott Ratchford, Jennifer Dartez, Greg Phillips, John Pilon, and Todd Felix for collecting the strips of rectal tissue from these elk. We would like to thank Cecily Powers for trimming the rectal biopsies. We would like to thank Robert Zink and Larry Ludden for embedding, Robert Zink and Dariush Ghazi for cutting, and Bruce Cummings for staining the brain, lymphoid tissue, and rectal biopsies. We would like to thank Mark Schoenbaum for his assistance with statistical evaluations. We would like to thank Dr. Katherine O'Rourke for consultation and review of this study. We would like to thank Dr. Charles Hibler for reviewing this manuscript. This project was partially funded by Specific Cooperative Agreement 58-5348-2-0678 with ARS/USDA, Pullman, WA, and Colorado State University Diagnostic Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO.


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From the College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80526 (Spraker), the US Department of Agriculture/Animal and Plant Health Inspection Service (USDA/APHIS), Veterinary Services, Fort Collins, CO 80521 (Gidlewski, Creekmore), the National Wildlife Research Center, USDA/APHIS, Wildlife Services, Fort Collins, CO 80521 (VerCauteren), the Animal Diseases Research Institute, Canadian Food Inspection Agency, Nepean, Ontario K2H 8P9, Canada (Balachandran), and the USDA/APHIS, Veterinary Services, Lincoln, NE 68516 (Munger). Back

a. Fisher Scientific, Houston TX. Back

b. DAKO CORP, Carpinteria CA. Back

c. Ventana Medical Systems, Inc., Tucson AZ. Back


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