PrP ^TSE Distribution in a Primate Model of Variant, Sporadic, and Iatrogenic Creutzfeldt-Jakob Disease

Abstract

Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), are neurodegenerative and fatal. Sporadic CJD (sCJD) can be transmitted between humans through medical procedures involving highly infected organs, such as the central nervous system. However, in variant CJD (vCJD), which is due to human contamination with the bovine spongiform encephalopathy (BSE) agent, lymphoreticular tissue also harbors the transmissible spongiform encephalopathy-associated prion protein (PrP TSE ), which poses a particularly acute risk for iatrogenic transmission. Two blood transfusion-related cases are already documented. In addition, the recent observation of PrP TSE in spleen and muscle in sCJD raised the possibility that peripheral PrP TSE is not limited to vCJD cases. We aimed to clarify the peripheral pathogenesis of human TSEs by using a nonhuman primate model which mimics human diseases. A highly sensitive enzyme-linked immunosorbent assay was adapted to the detection of extraneural PrP TSE . We show that affected organs can be divided into two groups. The first is peripheral organs accumulating large amounts of PrP TSE , which represent a high risk of iatrogenic transmission. This category comprises only lymphoreticular organs in the vCJD/BSE model. The second is organs with small amounts of PrP TSE associated with nervous structures. These are the muscles, adrenal glands, and enteric nervous system in the sporadic, iatrogenic, and variant CJD models. In contrast to the first set of organs, this low level of tissue contamination is not strain restricted and seems to be linked to secondary centrifugal spread of the agent through nerves. It might represent a risk for iatrogenic transmission, formerly underestimated despite previous reports of low rates of transmission from peripheral organs of humans to nonhuman primates (5, 10). This study provides an additional experimental basis for the classification of human organs into different risk categories and a rational re-evaluation of current risk management measures.Prion diseases are fatal disorders of both humans and animals and can be acquired, spontaneous, or genetic in origin (28). All forms of Creutzfeldt-Jakob disease (CJD) are infectious (5, 12), and transmission of sporadic CJD (sCJD) has occurred through cross-contamination from neurosurgical devices or through therapeutic usage of human central nervous system (CNS) tissues, causing over 267 iatrogenic CJD (iCJD) cases worldwide (6). With the appearance of variant CJD (vCJD), a new risk of iatrogenic transmission emerged, since the misfolded form of the prion protein which accumulates in transmissible spongiform encephalopathies (PrP TSE ) was found in peripheral organs, including lymphoid tissues and the rectum (32). Therefore, leukoreduction of blood units was implemented in 1999, and precautions have been recommended for gastrointestinal endoscopies (4). However, interhuman transmission of vCJD has probably already happened twice through blood transfusion from persons with preclinical vCJD (25,27). This demonst...

Detection of Disease-associated Prion Protein in the Optic Nerve and the Adrenal Gland of Cattle with Bovine Spongiform Encephalopathy by Using Highly Sensitive Immunolabeling Procedures

“…No specific background immunolabeling is detected in the optic nerve of a control animal immunostained with phosphate-buffered saline instead of the primary prion protein (PrP)-primary antibody using the TSA system (M). (Herzog et al 2005) were estimated to be 120 and 2500-10,000 times less, respectively, than the amounts present in brains. However, the proximal optic nerve of a vCJD patient contained extremely high levels of PrP Sc -only four times less than that found in the brain (Wadsworth et al 2001).…”

B Cells and Platelets Harbor Prion Infectivity in the Blood of Deer Infected with Chronic Wasting Disease

“…Subsequent studies utilizing confocal microscopy confirmed an association between PrP RES and immune cells (FDCs, tingible body macrophages, and B cells) and extended the repertoire of prion diseases with lymphoid involvement to include CWD and vCJD (42,55,60,66,67). B cells have been associated with PrP RES transport and/or deposition within the lymphoid system (9,10,18,22,23,32,43,56,64,66,81). The present study supports this contention in demonstrating that MAb 2-104 ϩ primarily B cells harvested from peripheral blood or retropharyngeal lymph nodes contain sufficient infectious prions to transmit CWD to native or transgenic hosts.…”

Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

“…Tissue preparation and purification of PrP Sc for gel electrophoresis PrP Sc purification of tissue was performed prior to western blot analysis as previously described (Bartz et al 2003(Bartz et al , 2005 with modifications based on the work of Herzog et al (2005). Briefly, tissues were weighed, minced with a razor blade, and mixed with digestion buffer (25 mM HEPES (pH 7 .…”