Halting the spread of human prion disease – exceptional measures for an exceptional problem

Abstract

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are uniformly fatal neurodegenerative diseases and include Transmissible Mink Encephalopathy in mink, scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) in cattle and large cats, Chronic Wasting Disease (CWD) in deer and Creutzfeldt Jakob disease (CJD) in humans. They are characterised by a long incubation period, normally several months or years, but without evidence of an infecting agent or an immune response to one.1 The exact mode of transmission of TSEs is a matter of debate, but it is known that a host protein, the prion protein (PrP), plays a central role in these diseases. The prion protein adopts two main conformations: a normal, cellular form (PrPc) expressed in most cells, and a disease-associated form (PrPsc), usually found in brain, spleen and lymph node follicular dendritic cells, especially in tonsils. The altered structure of PrPsc is characterised by its lower alpha-helical and higher beta-sheet content, and by its partial resistance to proteinase K digestion. It is thought that PrPsc replicates by acting as a conformational template, causing the host PrPc to adopt the PrPsc conformation. As disease develops, large protein fibrils (called scrapieassociated fibrils, which contain aggregated PrPsc molecules) are seen in neuronal and lymphoid tissues.2 In the absence of a unique nucleic acid or an immune response, detection of the agent and diagnosis of the disease is difficult. Moreover, it has been known for some time that some TSE strains are resistant to steam sterilisation and most other common disinfection procedures. Consequently, a number of cases of iatrogenic CJD have been attributed to the failure of cleaning and sterilising procedures to effectively decontaminate medical and surgical instruments.3 The BSE agent is especially resistant to steam sterilisation and recent work has shown that the variant CJD (vCJD) agent is similarly resistant, with the standard autoclave cycle currently in use in the UK’s national health Service (NHS) reducing titres in infected brain with an estimated titre of 109 infectious units/gram by only 2 or 3 orders of magnitude. As the disease-forming characteristics of the agent rely on its secondary structure and not on the integrity of a nucleic acid sequence, many sterilisation processes such as UV irradiation are ineffective. Moreover, other inactivation processes such as fixation with formalin and other aldehydes preserve the infectious nature of the agent as they cross-link proteins and thus lock in their secondary structure. This is unlike conventional infectious agents such as viruses which require structural fluidity in their proteins to enter the host and replicate. Furthermore, inadequate heating may accelerate dehydration, forming a protective layer which inhibits further inactivation.