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Biomedical subjects

Christina J Sigurdson

Publications and source records attributed to Christina J Sigurdson.

11 recordsLinked to original sources
PubMed2006

Chronic wasting disease.

Until recently, chronic wasting disease of cervids, the only prion disease affecting wildlife, was believed to be geographically concentrated to Colorado and Wyoming within the United States. However, increased surveillance has unveiled several additional pockets of CWD-infected deer and elk in 12 additional states and 2 Canadian provinces. Deer and elk with CWD have extensive aggregates of PrP(Sc) not only in the central nervous system, but also in peripheral lymphoid tissues, skeletal muscle, and other organs, perhaps influencing prion shedding. Indeed, CWD is transmitted efficiently among animals by horizontal routes, although the mechanism of spread is unknown. Genetic polymorphisms in the Prnp gene may affect CWD susceptibility, particularly at codon 225 (S/F) in deer and codon 132 (M/L) in elk. Since CWD infects free-ranging animals and is efficiently spread, disease management will be a challenge.

Animals↗
PubMed2006

Infectious prions in the saliva and blood of deer with chronic wasting disease.

A critical concern in the transmission of prion diseases, including chronic wasting disease (CWD) of cervids, is the potential presence of prions in body fluids. To address this issue directly, we exposed cohorts of CWD-naïve deer to saliva, blood, or urine and feces from CWD-positive deer. We found infectious prions capable of transmitting CWD in saliva (by the oral route) and in blood (by transfusion). The results help to explain the facile transmission of CWD among cervids and prompt caution concerning contact with body fluids in prion infections.

Animals↗
PubMed2006

Strain fidelity of chronic wasting disease upon murine adaptation.

Chronic wasting disease (CWD), a prion disease of deer and elk, is highly prevalent in some regions of North America. The establishment of mouse-adapted CWD prions has proven difficult due to the strong species barrier between mice and deer. Here we report the efficient transmission of CWD to transgenic mice overexpressing murine PrP. All mice developed disease 500 +/- 62 days after intracerebral CWD challenge. The incubation period decreased to 228 +/- 103 days on secondary passage and to 162 +/- 6 days on tertiary passage. Mice developed very large, radially structured cerebral amyloid plaques similar to those of CWD-infected deer and elk. PrP(Sc) was detected in spleen, indicating that murine CWD was lymphotropic. PrP(Sc) glycoform profiles maintained a predominantly diglycosylated PrP pattern, as seen with CWD in deer and elk, across all passages. Therefore, all pathological, biochemical, and histological strain characteristics of CWD appear to persist upon repetitive serial passage through mice. These findings indicate that the salient strain-specific properties of CWD are encoded by agent-intrinsic components rather than by host factors.

Amino Acid Sequence↗
PubMed2006

Prions in skeletal muscles of deer with chronic wasting disease.

The emergence of chronic wasting disease (CWD) in deer and elk in an increasingly wide geographic area, as well as the interspecies transmission of bovine spongiform encephalopathy to humans in the form of variant Creutzfeldt Jakob disease, have raised concerns about the zoonotic potential of CWD. Because meat consumption is the most likely means of exposure, it is important to determine whether skeletal muscle of diseased cervids contains prion infectivity. Here bioassays in transgenic mice expressing cervid prion protein revealed the presence of infectious prions in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk to prion exposure.

Animals↗
PubMed2004

Antiprion immunotherapy: to suppress or to stimulate?

Although human prion diseases are rare, they are invariably fatal, and treatments remain elusive. Hundreds of iatrogenic prion transmissions have occurred in the past two decades, and the bovine spongiform encephalopathy epidemic has raised concerns about prion transmission from cattle to humans. Research into therapeutics for prion disease is being pursued in several centres and prominently includes immunological strategies. Currently, the options that are being explored aim either to mobilize the innate and adaptive immune systems towards prion destruction or to suppress or dedifferentiate the lymphoreticular compartments that replicate prions. This article reviews the pathophysiology of prion diseases in mouse models and discusses their relevance to immunotherapeutic and immunoprophylactic antiprion strategies.

Adjuvants, Immunologic↗
PubMed2003

Other animal prion diseases.

In addition to bovine spongiform encephalopathy (BSE) of cattle and scrapie of sheep and goats, a few other animal prion diseases have been reported. These include feline spongiform encephalopathy of zoological and domestic cats (FSE) and transmissible spongiform encephalopathy (TSE) of zoological ruminants and non-human primates, as well as chronic wasting disease of deer and elk (CWD) and transmissible mink encephalopathy of farmed mink (TME). The origins of TSE in cats, zoo bovids, and non-human primates are clearly linked to the BSE epidemic; however, the origins of CWD and TME are less clear, but are not epidemiologically linked to the BSE epidemic. Here we review the epidemiology, transmission, clinical features and pathology of these other animal prion diseases.

Animals↗
PubMed2002

PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer.

Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt-Jakob disease in which the abnormal prion protein isoform, PrP(CWD), accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrP(CWD), we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrP(CWD) primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrP(CWD), potentially in association with immunoglobulin or complement, or PrP(C) conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrP(CWD), reflecting either phagocytosis of PrP(CWD) on FDC processes, apoptotic FDC or B cells, or actual PrP(CWD) replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrP(CWD) distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrP(CWD) was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrP(CWD) accumulates primarily extracellularly and associated with FDCs and possibly B cells - a finding which raises questions as to the cells responsible for pathological prion production.

Animals↗
PubMed2002

Preclinical diagnosis of chronic wasting disease in captive mule deer (Odocoileus hemionus) and white-tailed deer (Odocoileus virginianus) using tonsillar biopsy.

The usefulness of tonsillar biopsy on live deer for preclinical diagnosis of the transmissible spongiform encephalopathy chronic wasting disease (CWD) was evaluated. Disease was tracked in a CWD-endemic herd using serial tonsillar biopsies collected at 6 to 9 month intervals from 34 captive mule deer (Odocoileus hemionus) and five white-tailed deer (O. virginianus). Tonsillar biopsies were examined for accumulation of PrP(CWD), the protein marker for infection, using immunohistochemical (IHC) staining. 26/34 (76%) mule deer and 4/5 (80%) white-tailed deer had PrP(CWD) accumulation in tonsillar biopsies; CWD was subsequently confirmed by post-mortem examination in all 30 of these tonsillar-positive deer. Six mule deer with IHC-negative tonsillar biopsies had positive brain and tonsillar IHC staining upon death 12 to 40 months following the last biopsy. PrP(CWD) accumulation in tonsillar biopsy was observed 2 to 20 months before CWD-related death and up to 14 months before onset of clinical signs of CWD. Tonsillar biopsies from 3-month-old mule deer (n=6) were IHC negative, but PrP(CWD) accumulation was detected in tonsillar biopsies from 7/10 mule deer by 19 months of age. Tonsillar biopsy evaluated with IHC staining is a useful technique for the preclinical diagnosis of CWD in live mule deer and white-tailed deer when intensive management approaches are possible.

Animals↗
PubMed2001

PrP(CWD) in the myenteric plexus, vagosympathetic trunk and endocrine glands of deer with chronic wasting disease.

Accumulated evidence in experimental and natural prion disease systems supports a neural route of infectious prion spread from peripheral sites of entry to the central nervous system. However, little is known about prion trafficking routes in cervids with a naturally occurring prion disease known as chronic wasting disease (CWD). In the brain, the pathogenic isoform of the prion protein (PrP(CWD)) accumulates initially in the dorsal motor nucleus of the vagus nerve. To assess whether alimentary-associated neural pathways may play a role in prion trafficking, neural and endocrine tissues from mule deer naturally infected with CWD (n=6) were examined by immunohistochemistry. PrP(CWD) was detected in the myenteric plexus, vagosympathetic trunk, nodose ganglion, pituitary, adrenal medulla and pancreatic islets. No to scant PrP(CWD) staining was detected in other nerves or ganglia (brachial plexus, sciatic nerve, gasserian ganglion, coeliac ganglion, cranial cervical ganglion, spinal nerve roots) of CWD-positive deer and no PrP(CWD) was detected in nerves or endocrine tissues from 11 control deer. These findings suggest that: (i) transit of PrP(CWD) in nerves, either centrifugally or centripetally, is one route of prion trafficking and organ invasion and (ii) endocrine organs may also be targets for cervid pathogenic prion accumulation.

Animals↗
PubMed1999

Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus).

Mule deer fawns (Odocoileus hemionus) were inoculated orally with a brain homogenate prepared from mule deer with naturally occurring chronic wasting disease (CWD), a prion-induced transmissible spongiform encephalopathy. Fawns were necropsied and examined for PrPres, the abnormal prion protein isoform, at 10, 42, 53, 77, 78 and 80 days post-inoculation (p.i.) using an immunohistochemistry assay modified to enhance sensitivity. PrPres was detected in alimentary-tract-associated lymphoid tissues (one or more of the following: retropharyngeal lymph node, tonsil, Peyer's patch and ileocaecal lymph node) as early as 42 days p.i. and in all fawns examined thereafter (53 to 80 days p.i.). No PrPres staining was detected in lymphoid tissue of three control fawns receiving a control brain inoculum, nor was PrPres detectable in neural tissue of any fawn. PrPres-specific staining was markedly enhanced by sequential tissue treatment with formic acid, proteinase K and hydrated autoclaving prior to immunohistochemical staining with monoclonal antibody F89/160.1.5. These results indicate that CWD PrPres can be detected in lymphoid tissues draining the alimentary tract within a few weeks after oral exposure to infectious prions and may reflect the initial pathway of CWD infection in deer. The rapid infection of deer fawns following exposure by the most plausible natural route is consistent with the efficient horizontal transmission of CWD in nature and enables accelerated studies of transmission and pathogenesis in the native species.

Animals↗