Prion Exposure Research Articles

Neuroendocrine cultured cells counteract persistent prion infection by down-regulation of PrP c

Cell models for prion diseases are mainly of neuronal origin. However, the pathological isoform PrP Sc of cellular prion protein (PrP c) and prion infectivity are found in a variety of extraneural tissues in prion diseases. Although many cell types are not able to propagate PrP Sc, little is known about cellular mechanism counteracting prion infection. It is desirable to identify neuronal or non-neuronal cell models that restrict PrP Sc generation or propagate PrP Sc only transiently. Neuroendocrine cells are derived from tumours forming the interface between endocrine and nervous system. We investigated the susceptibility of such murine cell lines to prion infection, which were in principle able to transiently propagate PrP Sc. Surprisingly and in contrast to neuronal cells prion infection was abrogated by rapid and PrP Sc-specific down-regulation of PrP c expression upon exposure to prion-infected material. Cell lines described here provide novel models for studying PrP c regulation and intrinsic cellular defence mechanisms upon prion exposure.

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.

A New Ossicle Homograft Inactivation/Preservation Procedure: Clinical Results

A new NaOH-autoclaving inactivation/preservation procedure (IPP) for ossicle homografts, complying with the actual infectious disease guidelines, has been developed and used in our institution for 5 years. This study compares the clinical and audiological results of middle ear reconstruction using the new NaOH-autoclaving inactivated ossicle homografts (22 patients) and the previously used cialit-formaldehyde inactivation procedure (28 patients). During the follow-up period, no homograft extrusion, resorption or disease transmission was observed either for the NaOH-autoclaving or for the cialit-formaldehyde protocol. A postoperative air-bone gap of less than 20 dB in 44% and a postoperative hearing improvement of 10–50 dB in 70% of patients complies with the published success rates of homograft ossiculoplasty in the literature. The analysis and comparison of both tested IPP-patient groups showed no statistically significant differences in the clinical and the audiological results. The NaOH-autoclaving inactivation/preservation protocol should increase ossicle homograft safety even with respect to prion exposure. The good anatomic and audiological long-term results of the new IPP protocol confirm homograft ossicles as a valid and inexpensive approach for middle ear reconstruction.

Scratch-wounding renders cultivated cells less permissive to prion infection

Using permissive cell lines of epithelial or neuroglial origin, we found that scratch-wounding a small proportion of the recipient cells prior to prion exposure strongly reduced the cell culture’s susceptibility to infection. We provide evidence suggesting that wound-triggered inhibition of prion infection was mediated by the release of nucleotides in the extracellular medium of injured cultures. While cell wounding or ATP treatment of unwounded target cells inhibited de novo infection, we found that they had no effect on steady-state infected cultures, indicating that these treatments affect the early stages of infection. These findings support the view that cells have the capacity to modulate their permissiveness to prion infection in response to external stimuli, such as a signalling molecule.

Serial EEG findings in sporadic and iatrogenic Creutzfeldt–Jakob disease

Objective: To study temporal and spatial development of EEG patterns in sporadic and iatrogenic Creutzfeldt–Jakob disease patients. Methods: Temporal and spatial development of EEG patterns in 4 patients with sporadic Creutzfeldt–Jakob disease and 2 patients with iatrogenic Creutzfeldt–Jakob disease due to implantation of contaminated brain depth electrodes were investigated. A total of 56 EEGs were analyzed, over time spans ranging from 1272 to 3 days prior to death. Results: Frontal intermittent rhythmical delta activity (FIRDA) was seen at early timepoints in 4/6 patients and might represent an early EEG pattern that is associated, with human prion diseases. EEG patterns associated with CJD are sensitive to midazolam. Initial EEG changes were seen at the site of prion exposure in iatrogenic Creutzfeldt–Jakob disease patients, before they could be observed at distant sites, suggesting that prion disease was initiated at the site of prion exposure. Conclusions: Serial EEG recordings are a valuable tool not only in the early diagnosis of sporadic CJD, but also in the determination of prion exposure in iatrogenic Creutzfeldt–Jakob disease. Significance: FIRDA occur at an early stage of CJD and are progressively replaced by the classical PSWC. The EEG patterns of CJD are sensitive to midazolam. The initial EEG changes in iatrogenic CJD are seen at the site of prion exposure.

Subclinical prion infection in humans and animals.

Transmission of prion diseases between mammalian species is limited by a so-called 'species' or 'transmission' barrier. Recognition of prion transmission usually relies on the appearance of clinical symptoms in inoculated animals and the interval between inoculation and appearance of clinical disease is designated incubation period. At some point during this clinically silent period, neuropathological and biochemical changes as well as accumulation of prions in the brain can be detected and this stage can be called preclinical prion disease. Recently, several lines of evidence have suggested that subclinical forms of prion disease exist, in which high levels of infectivity and PrP(Sc) are found in animals that do not develop clinically apparent disease during a normal life-span. Such asymptomatic prion 'carrier' states challenge our current understanding of pathogenesis as well as of the molecular basis of barriers to transmission. Subclinical as well as preclinical/clinical prion disease may be relevant when analysing the risk to public health of potential sources of prion exposure.

Anti-prion antibodies for prophylaxis following prion exposure in mice

Prion disease is characterized by a conformational change of the normal form of the prion protein (PrP C) to the scrapie-associated form (PrP Sc). Since the emergence of new variant Creutzfeldt-Jakob disease a potentially large human population is at risk for developing prion disease. Currently, no effective treatment or form of post-exposure prophylaxis is available for prion disease. We recently showed that active immunization with recombinant PrP prolongs the incubation period of scrapie. Here we show that anti-PrP antibodies following prion exposure are effective at increasing the incubation period of the infection. Stimulation of the immune system is an important therapeutic target for the prion diseases, as well as for other neurodegenerative illnesses characterized by abnormal protein conformation.

Immunization Delays the Onset of Prion Disease in Mice

The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease.