“Slow” infectious diseases are caused by a heterogeneous group of agents containing both conventional viruses and unconventional agents that are not viruses (e.g., prions). Prions are protein-containing particles with no detectable nucleic acid that are highly resistant to inactivation by heat, formaldehyde, and ultraviolet light at doses that will inactivate viruses. Note that prions are resistant to the temperatures usually employed in cooking, a fact that may be important in their suspected ability to be transmitted by food (see variant Creutzfeldt-Jakob disease [vCJD] later). Prions are, however, inactivated by protein- and lipid-disrupting agents such as phenol, ether, NaOH, and hypochlorite (see Chapter 28).
The prion protein is encoded by a normal cellular gene and is thought to function in a signal transduction pathway in neurons.
There is some evidence that the function of the normal cellular prion protein is to regulate the N-methyl-D-aspartate receptor on the postsynaptic terminal by binding copper ions.
The normal prion protein (known as PrPC, or prion protein cellular) has a significant amount of alpha-helical conformation. When the alpha-helical conformation changes to a beta-pleated sheet (known as PrPSC, or prion protein scrapie), these abnormal forms aggregate into filaments, which disrupt neuron function and cause cell death. Prions, therefore, “reproduce” by the abnormal beta-pleated sheet form recruiting normal alpha-helical forms to change their conformation. Note that the normal alpha-helical form and the abnormal beta-pleated sheet form have the same amino acid sequence. It is only their conformation that differs. A specific cellular RNA enhances this conformational change. Prions are described in more detail in Chapter 28.
Pathogenic prion proteins can be thought of conceptually as misfolded proteins. These misfolded proteins not only cause CJD in humans and “mad cow” disease in cattle but are suspected of being involved in the pathogenesis of other important diseases of the central nervous system, such as Alzheimer’s disease and Parkinson’s disease.
In humans, the “slow” agents cause central nervous system diseases characterized by a long incubation period, a gradual onset, and a progressive, invariably fatal course. There is no antimicrobial therapy for these diseases. Note that the term slow refers to the disease, not to the rate of replication of those viruses that cause these slow diseases. The replication rate of these viruses is similar to that of most other viruses.
The human prion-mediated diseases (e.g., kuru and CJD) are called transmissible spongiform encephalopathies (TSE). The term spongiform refers to the spongy, Swiss cheese-like holes seen in the brain parenchyma that are caused by the death of the neurons (Figure 44–1). No virus particles are seen in the brain of people with these diseases.
Prion-mediated spongiform encephalopathy (mad cow disease). Two arrows point to the spongiform appearance (Swiss cheese-like holes) in the brain of a cow with mad cow disease. ...