Neuroinvasion in sheep transmissible spongiform encephalopathies: the role of the haematogenous route

Sisó, Sílvia; Jeffrey, Martin; González, Lorenzo

doi:10.1111/j.1365-2990.2008.00978.x

Cited by 64 publications

(73 citation statements)

References 39 publications

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“…13,45,61,62 An alternative hypothesis for neuroinvasion suggests that the agent can spread into the brain through the circumventricular organs, where the blood-brain barrier is absent. 54 However, the ability to detect PrP Sc in the …”

Section: Discussionmentioning

confidence: 99%

Experimental Classical Bovine Spongiform Encephalopathy

et al. 2010

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Tissues from sequential-kill time course studies of bovine spongiform encephalopathy (BSE) were examined to define PrP immunohistochemical labeling forms and map disease-specific labeling over the disease course after oral exposure to the BSE agent at two dose levels. Study was confined to brainstem, spinal cord, and certain peripheral nervous system ganglia-tissues implicated in pathogenesis and diagnosis or disease control strategies. Disease-specific labeling in the brainstem in 39 of 220 test animals showed the forms and patterns observed in natural disease and invariably preceded spongiform changes. A precise temporal pattern of increase in labeling was not apparent, but labeling was generally most widespread in clinical cases, and it always involved neuroanatomic locations in the medulla oblongata. In two cases, sparse labeling was confined to one or more neuroanatomic nuclei of the medulla oblongata. When involved, the spinal cord was affected at all levels, providing no indication of temporal spread within the cord axis or relative to the brainstem. Where minimal PrP labeling occurred in the thoracic spinal cord, it was consistent with initial involvement of general visceral efferent neurons. Labeling of ganglia involved only sensory ganglia and only when PrP was present in the brainstem and spinal cord. These experimental transmissions mimicked the neuropathologic findings in BSE-C field cases, independent of dose of agent or stage of disease. The model supports current diagnostic sampling approaches and control measures for the removal and destruction of nervous system tissues in slaughtered cattle.

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Section: Discussionmentioning

confidence: 99%

Experimental Classical Bovine Spongiform Encephalopathy

et al. 2010

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“…Early accumulation of scrapie in the CVO has prompted some researchers to propose that because the CVO is devoid of the blood-brain barrier, prions can cross unhampered from the blood to the brain and then on to regional lymph nodes. 15 The data suggests that in the earlier stages of disease, the intact ependymal and CVO appear to sequester PrP CWD and prevent infiltration of PrP CWD into the CSF. It is therefore reasonable to propose that in the latter stages of disease, with obex scores greater than 9, the PrP CWD begins to leak through the epemdyma, allowing PrP CWD access to the CSF.…”

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confidence: 94%

“…8,12,13,23 Chronic wasting Free range -0 disease has been detected in blood, 6 and studies done in sheep demonstrate that intravenous inoculation with scrapie results in neuroinvasion and disease indistinguishable from other routes of infection. 15 It has been postulated in the literature that the circumventricular organs (CVO) in the brain could be a site of entry for prions from the blood into the brain. 15 The CVO are specialized structures that line the third and fourth ventricles of the brain and are considered to be absent of the "blood-brain barrier."…”

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confidence: 99%

“…15 The CVO are specialized structures that line the third and fourth ventricles of the brain and are considered to be absent of the "blood-brain barrier." 5 As has been seen with scrapie in sheep, 15 PrP CWD can be detected in the CVO, with the exception of the choroid plexus, in nonclinical deer and elk with obex scores greater than 9 (with the obex scoring system, clinical signs are usually not observed until obex scores of 9 or 10 are achieved (unpublished data, 2005). Early accumulation of scrapie in the CVO has prompted some researchers to propose that because the CVO is devoid of the blood-brain barrier, prions can cross unhampered from the blood to the brain and then on to regional lymph nodes.…”

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Detection of prion protein in the cerebrospinal fluid of elk (Cervus canadensis nelsoni) with chronic wasting disease using protein misfolding cyclic amplification

Nichols

Spraker²,

Gidlewski³

et al. 2012

J VET Diagn Invest

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Abstract. Cerebrospinal fluid (CSF) has been examined as a possible source for preclinical diagnosis of prion diseases in hamsters and sheep. The present report describes the detection of chronic wasting disease (CWD) in the CSF of elk and evaluates its usefulness as an antemortem test for CWD. The CSF from 6 captive and 31 free-ranging adult elk was collected at necropsy and evaluated for the presence of the abnormal isoform of the prion protein that has been associated with CWD (PrP CWD ) via protein misfolding cyclic amplification. Additionally, the obex from each animal was examined by immunohistochemistry (IHC). Four out of 6 captive animals were CWD-positive and euthanized due to signs of terminal CWD. The remaining 2 were CWD negative. None of the 31 free-range animals showed overt signs of CWD, but 12 out of 31 tested positive for CWD by IHC. Protein misfolding cyclic amplification detected PrP CWD from 3 of the 4 captive animals showing clinical signs of CWD and none of the nonclinical animals that were CWD positive by IHC. The data suggests that CWD prions can be detected in the CSF of elk, but only relatively late in the course of the disease.

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“…34,35 These findings suggest the presence of varying infectivity in rodents and ruminants. Interestingly, highly purified radioactively labeled murine PrP Sc could pass through the mouse blood-brain barrier, 36 suggesting the possible existence of cell-free PrP Sc in the blood.…”

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confidence: 99%

Magnetic microparticle-based multimer detection system for the detection of prion oligomers in sheep

Lim

Kim²,

Lee

et al. 2015

IJN

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Transmissible spongiform encephalopathies (TSEs) are zoonotic fatal neurodegenerative diseases in animals and humans. TSEs are commonly known as bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt–Jakob disease in humans. The putative transmissible agents are infectious prion proteins (PrP Sc ), which are formed by the conversion of the normal prion protein on the glycoprotein cell surface in the presence of other PrP Sc . Reports of the transmission of TSEs through blood raised considerable concern about the safety of blood and blood products. To address this issue, many laboratories attempted to develop a sensitive and accurate blood diagnostic test to detect PrP Sc . Previously, we reported that, compared to normal controls, the multimer detection system (MDS) was more efficient in detecting PrP Sc in infected hamster brain homogenate, mouse plasma spiked with purified PrP Sc from scrapie mouse brain, and scrapie-infected hamster plasmas. MDS differentiates prion multimers from the cellular monomer through the multimeric expression of epitopes on prion multimers, in contrast to the monomeric form. In this study, MDS detected PrP Sc in plasma samples from scrapie-infected sheep expressing clinical symptoms, demonstrating 100% sensitivity and specificity in these samples. Plasma samples from asymptomatic lambs at the preclinical stage (8-month-old naturally infected offspring of scrapie-infected parents expressing a highly susceptible genotype) tested positive with 50% sensitivity and 100% specificity. In the first of two coded analyses using clinical scrapie-infected sheep and normal healthy samples, MDS successfully identified all but one of the clinical samples with 92% sensitivity and 100% specificity. Similar results were obtained in the second coded analysis using preclinical samples. MDS again successfully identified all but one of the samples with 87% sensitivity and 100% specificity. The false-negative sample was subjected to a protease pretreatment. In conclusion, MDS could accurately detect scrapie in plasma samples at both preclinical and clinical stages. From these studies, we conclude that MDS could be a promising tool for the early diagnosis of TSEs from blood samples.

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Neuroinvasion in sheep transmissible spongiform encephalopathies: the role of the haematogenous route

Abstract: The haematogenous route, therefore, can represent a parallel or alternative pathway of neuroinvasion to ascending infection via the ENS/autonomic nervous system.

Cited by 64 publications

References 39 publications

Experimental Classical Bovine Spongiform Encephalopathy

Experimental Classical Bovine Spongiform Encephalopathy

Detection of prion protein in the cerebrospinal fluid of elk (Cervus canadensis nelsoni) with chronic wasting disease using protein misfolding cyclic amplification

Magnetic microparticle-based multimer detection system for the detection of prion oligomers in sheep

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