Valerie R. McElliott’s research while affiliated with University of Georgia and other places

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Publications (3)


Accumulations of PrPSc in the brain of recipient ewes
(A) Rank scores of PrPSc accumulation for each recipient ewe by brain region: G1—caudal medulla at the obex, G2—cerebellar cortex, G3—superior colliculus, G4/5—hypothalamus and medial thalamus, G6—hippocampus, G7—septum, G8—cerebral cortex at level of G4/5, G9—forebrain cortex at level of G7, W1—cerebellar white matter, W2—mesencephalic tegmentum. G1 was plotted as a mean of the rank scores to represent the two brain sections. G6 and G7 were plotted as a mean of the rank scores to include all the gray matter neuroanatomy in the respective section. (B) Punctate to globular extracellular PrPSc in spinocerebellar nerve fiber tract. Animal 3917, caudal medulla, IHC. (C) Absent PrPSc in the dorsal motor nucleus of the vagus nerve. Animal 3917, caudal medulla, IHC. (D) Patchy but diffuse, coalescing finely granular PrPSc in the molecular layer of the cerebellum (solid arrow), and punctate PrPSc in the white matter of the folia (solid arrowheads). Rare PrPSc in the granular layer (open arrowhead). Animal 3917, cerebellum, IHC. (E) Plaques (dashed ellipses) in the corona radiata with displacement of nerve fibers and mild gliosis (solid arrowheads); H&E. (F) PrPSc multicentric aggregates (dashed ellipses) coinciding with the localization of plaques on H&E; IHC. (E, F) Animal 3916, forebrain.
Western blots demonstrating stable experimental transmission of ARR/ARR atypical scrapie to ARR/ARR sheep and Tg338 ovinized mice
A) Brain homogenate from the original donor sheep (1204–02) shows an anti-PrP western blot profile indicative of atypical scrapie following treatment with proteinase K (PK). Brain homogenates from a sheep positive for classical scrapie (4533), and scrapie-naïve sheep (4509, 4759) are shown for comparison. B) Western blot of brain homogenates from the original atypical scrapie donor (1204–02), recipient ewes (3913, 3914, 3916, 3917), and a scrapie-naïve sheep (4759). C) Western blot of brain homogenates from Tg338 ovinized mice inoculated with brain homogenate from the original atypical scrapie donor (1204–02). Passage 1 (P1) mice were inoculated with brain homogenate from 1204–02 and Passage 2 (P2) mice were inoculated with brain homogenates from P1 mice. D) Western blot of brain homogenates from Tg338 ovinized mice inoculated with brain homogenate from recipient ewes (representative blot from ewe 3916 shown). Western blots labeled with molecular weight markers of 20, 40 kDa.
Accumulation of non-infective PrPres in the placentas of ARR/ARR ewes infected by atypical scrapie from a US ARR/ARR sheep
A) PrPSc was not detected in cotyledons (Ct.) from infected ewes (3913, 3914, 3916, 3917) by immunohistochemical staining; note red staining in cotyledon from a sheep with classical scrapie shown for comparison. B) Anti-PrP western blot showing accumulation of PrPres in cotyledons from infected ewes. Brain homogenate (Br.) from ewe 3913 shown for comparison. C) Anti-PrP western blot showing lack of PrPres in brain homogenates from Tg338 mice inoculated with homogenates of cotyledons containing PrPres (Ct.–M); inocula were prepared from the same cotyledons shown in (B). Brain homogenate of passage 2 mouse (Br.–M*) from original atypical scrapie donor shown for comparison. Western blots labeled with molecular weight markers of 20, 40 kDa. D,E) The proportion of cotyledons containing PrPres, detected via western blot, increased with the ages of the inoculated ewes.
Mouse bioassay of brain or placenta cotyledon homogenates (10% w/v)
PrP in placental tissue following experimental transmission of atypical scrapie in ARR/ARR sheep is not infectious by Tg338 mouse bioassay
  • Article
  • Full-text available

January 2022

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28 Reads

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1 Citation

Robert B. Piel

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Valerie R. McElliott

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Nor98-like atypical scrapie is a sporadic disease that affects the central nervous system of sheep and goats that, in contrast to classical scrapie, is not generally regarded as naturally transmissible. However, infectivity has been demonstrated via bioassay not only of brain tissue but also of certain peripheral nerves, lymphoid tissues, and muscle. This study examines placental tissue, a well characterized route of natural transmission for classical scrapie. Further, this study was conducted in sheep homozygous for the classical scrapie resistant ARR genotype and is the first to characterize the transmission of Nor98-like scrapie between homozygous-ARR sheep. Nor98-like scrapie isolated from a United States ARR/ARR sheep was transmitted to four ARR/ARR ewes via intracerebral inoculation of brain homogenate. These ewes were followed and observed to 8 years of age, remained non-clinical but exhibited progression of infection that was consistent with Nor98-like scrapie, including characteristic patterns of PrPSc accumulation in the brain and a lack of accumulation in peripheral lymphoid tissues as detected by conventional methods. Immunoblots of placental tissues from the infected ewes revealed accumulation of a distinct conformation of PrPres, particularly as the animals aged; however, the placenta showed no infectivity when analyzed via ovinized mouse bioassay. Taken together, these results support a low risk for natural transmission of Nor98-like scrapie in ARR/ARR sheep.

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Figure 6
Select Gene Expression Across Variable PrPSc Permissive Ovine Microglia

August 2019

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15 Reads

Background: Transmissible spongiform encephalopathies (TSEs) are a group of fatal, neurodegenerative diseases that affect multiple species, including sheep, cattle, and humans. A misfolded, pathogenic isoform (PrPD) of the normal, host-encoded, cellular prion protein (PrPC) is the causative agent for TSEs. While there have been advances in understanding TSEs, antemortem diagnostic tests are limited in many species, and there are no effective treatment protocols. Filling these reagent gaps will require knowledge of the molecular pathophysiology of PrPD accumulation. Previous work has suggested that the extracellular matrix (i.e., fibronectin 1) and physiological functions (i.e., cell division) maybe key factors for cellular prion permissibility, at least in specific cell culture models. Using a natural scrapie isolate, six immortalized, ovine microglial clones, of varying permissiveness to classical scrapie were evaluated for differential gene expression in seven genes based on previous RNASeq studies (fibronectin 1 [FN1], follistatin-like 1 [FSTL1], osteonectin [SPARC], survivin [BIRC5], syndecan 4 [SDC4], AXL receptor tyrosine kinase [AXL], and prion protein [PRNP]), and to determine correlations with prion permissibility. Results: Significant differential gene expression was frequently observed for survivin, follistatin-like 1 and osteonectin between clones, and when evaluated relative to PRNP expression. However, only fibronectin 1 and survivin were significantly correlated with prion permissibility, and only when evaluated relative to PRNP expression. Inoculation had a significant effect on follistatin-like 1, syndecan 4, and osteonectin. Conclusions: Similar to previous studies in other systems, fibronectin and mitotic rate show promise as potential determinants of prion permissibility in ovine microglia. As determinants of prion permissibility, the expression of fibronectin 1 and survivin coupled with PRNP could be utilized as biomarkers for detection of prion permissibility phenotype in ovine microglia, and perhaps other cell culture models of prion disease.


Correlation of Cellular Factors and Differential Scrapie Prion Permissiveness in Ovine Microglia

July 2017

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15 Reads

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3 Citations

Virus Research

Prion diseases are fatal neurodegenerative disorders by which the native cellular prion protein (PrPC) is misfolded into an accumulating, disease-associated isoform (PrPD). To improve the understanding of prion pathogenesis and develop effective treatments, it is essential to elucidate factors contributing to cellular permissiveness. We previously isolated five clones from an immortalized subline of ovine microglia, two of which had demonstrated differential permissiveness to a natural isolate of sheep scrapie and distinct transcriptomic profiles. To more robustly identify factors contributing to this activity, relative permissiveness, cell proliferation, selected gene transcript level, and matrix metalloproteinase 2 (MMP2) activity were compared amongst all five clones. Differences in cell proliferation were not detected between clones; however, significant correlations were identified between relative permissiveness and genes associated with cell growth (i.e., RARRES1 and PTN), protein degradation (i.e., CTSB and SQSTM1), and heparin binding (i.e., SEPP1). MMP2 activity varied amongst clones, but did not correlate with permissiveness. These associations support the contribution of cell division and protein degradation on the permissiveness of cultured ovine microglia to PrPD.

Citations (2)


... The wether was a second-generation relative of a ewe experimentally inoculated with atypical (Nor98-like) scrapie. 1 The inoculated ewe (the grandparent of the presenting patient) became infected with atypical scrapie but never developed clinical signs despite reaching 7 years of age. First-and second-generation offspring of these ewes, including the presenting patient, except for a rectal temperature of 105.6°F, which was unresponsive to NSAIDs. ...

Reference:

B-cell leukemia in an adult sheep
PrP in placental tissue following experimental transmission of atypical scrapie in ARR/ARR sheep is not infectious by Tg338 mouse bioassay

... Other potential receptors include the 37 kDa/67 kDa laminin receptor (LRP/LR) [95] and low-density lipoprotein receptorrelated protein 1 (Lrp1) [90]. Uptake is not sufficient for infection and also cells lacking PrP C efficiently internalize external PrP Sc [56,89,90,96]. Genetic and chemical manipulation of endocytosis pathways demonstrated that prions are preferentially taken up by clathrinand caveolin-independent routes or are able to bypass these routes when blocked [28]. ...

Correlation of Cellular Factors and Differential Scrapie Prion Permissiveness in Ovine Microglia
  • Citing Article
  • July 2017

Virus Research