Prions - causative agents of prion diseases

Slow viral infections are characterized by special criteria:

• unusually long incubation period (months, years);
• a kind of defeat of organs and tissues, mainly the central nervous system;
• slow steady progression of the disease;
• an unavoidable lethal outcome.

Some pathogens of acute viral infections can also cause slow viral infections. For example, the measles virus sometimes causes PSES, and the rubella virus - progressive congenital rubella and rubella panencephalitis.

A typical slow viral infection of animals is caused by virus visna / medi, which belongs to retroviruses. It is the causative agent of slow viral infection and progressive pneumonia of sheep. The white matter of the brain is destroyed , paralysis develops (visna - withering); there is a chronic inflammation of the lungs and spleen.

Similar diseases due to slow virus infections cause prions - pathogens of prion infections. Prion diseases are a group of progressive disorders of the human and animal CNS. People have disrupted the function of the central nervous system, there are changes in personality, movement disorders. Symptoms of the disease usually last from several months to several years, ending fatal. Previously, prion infections were considered together with the so-called pathogens of slow viral infections.

Some agents that cause prion diseases are accumulated first in lymphoid tissues. Prions entering the brain accumulate in it in large quantities, causing amyloidosis (extracellular disproteinosis, characterized by the deposition of amyloid with the development of atrophy and sclerosis of tissue) and astrocytosis (proliferation of astrocytic neuroglia, hyperproductive glial fibers). Fibrils, protein or amyloid aggregates and spongiform changes in the brain (transmissible spongiform encephalopathies) are formed. As a result, behavior changes, coordination of movements is disrupted, exhaustion with fatal outcome develops. Immunity is not formed. Prion diseases are related to conformational diseases that develop as a result of incorrect folding (a violation of the correct conformation) of the cellular protein necessary for the normal functioning of the organism. The ways of transferring prions are diverse:

• alimentary route - infected products of animal origin, nutritional supplements from raw bovine organs, etc .:
• transmission with blood transfusion, administration of animal products, transplantation of organs and tissues, use of infected surgical and dental instruments;
• transmission through immunobiological drugs (known to infect PrpP '' '1500 sheep brain formulvaccine from sick sheep).

Pathological prions, having got into the intestines, are transported to the blood and lymph. After peripheral replication in the spleen, appendix, tonsils and other lymphoid tissues, they are transferred to the brain via peripheral nerves (neuroinvasia). Probably direct penetration of prions into the brain through the blood-brain barrier. Previously, it was believed that the central nervous system is the only tissue in which pathological prions accumulate, but studies have emerged that changed this hypothesis. It turned out that the accumulation of prions in the spleen is associated with the increase and functioning of follicular dendritic cells.

[1], [2], [3], [4], [5], [6], [7],

Properties of prions

The cellular normal isoform of prion protein with a molecular weight of 33-35 kD is determined by the prion protein gene (prion gene-PrNP is on the 20th chromosome of a human). A normal gene appears on the surface of the cell (anchored in the membrane by the glycoprotein molecule), is sensitive to the protease. It regulates the transmission of nerve impulses, diurnal cycles, oxidation processes, participates in the metabolism of copper in the central nervous system and in the regulation of the division of bone marrow stem cells . In addition, the prion gene is found in the spleen, lymph nodes, skin, GIT and follicular dendritic cells.

Proliferation of pathological prions

The transformation of prions into altered forms occurs when the kinetically controlled equilibrium between them is disturbed. The process is enhanced when the amount of pathological (PrF) or exogenous prion increases. PrP is a normal protein anchored in the cell membrane. PrP 'is a globular hydrophobic protein, which forms aggregates with itself and with PrF "on the surface of the cell: as a result, PrP' is converted to PrF" and the cycle continues. The pathological form of PrF "" accumulates in the neurons, giving the cell a spongy appearance.

Kuru

Prion disease, formerly prevalent among the Papuans (translated as trembling or shaking) in the eastern part of the island of New Guinea. Infectious properties of the disease proved K. Gaidushek. The causative agent is transmitted by food as a result of ritual cannibalism - eating insufficiently thermally processed, infected prions of the brain dead relatives. As a result of the defeat of the central nervous system, movements, gait, shivering, euphoria ("laughing death") are disturbed. The incubation period lasts 5-30 years. A year later the patient dies.

Creutzfeldt-Jakob disease

Prion disease, occurring in the form of dementia, visual and cerebellar disorders and motor disorders with fatal outcome in 4-5 months of the disease in the classical version of Creutzfeldt-Jakob disease and after (3-14 months with a new variant of Creutzfeldt-Jacob disease.) The incubation period can reach 20. There are different ways of infection and the causes of the disease:

• when using insufficiently thermally processed products of animal origin, for example meat, brain cows, patients with bovine spongiform encephalopathy;
• for the transplantation of tissues, for example the cornea of the eye, blood transfusion, the use of hormones and other biological active substances of animal origin, the use of catgut, contaminated or insufficiently sterilized surgical instruments, prozection manipulations;
• for hyperproduction of PrP and other states that stimulate the process of transformation of PrP 'into PrF. "

The disease can also develop as a result of a mutation or insertion in the prion gene region. The family character of the disease is widespread as a result of a genetic predisposition to Creutzfeldt-Jakob disease. With a new variant of Creutzfeldt-Jakob disease, disorders develop at a younger age (mean age 28 years), in contrast to the classical variant (mean age 65 years). With a new variant of Creutzfeldt-Jakob disease, abnormal prionic protein accumulates not only in the central nervous system, but also in lymphoreticular tissues, including in the tonsils.

[8], [9], [10], [11]

The Gerstmann-Streussler-Sheinker Syndrome

Hereditary prion disease, which occurs with dementia, hypotension, swallowing (dysphagia), dysarthria. Often bears a family character. The incubation period is from 5 to 30 years. The disease occurs in 50-60 years, its duration varies from 5 to 13 years.

Hereditary mortal insomnia

Autoimmune disease with progressive insomnia, sympathetic hyperreactivity (hypertension, hyperthermia, hyperhidrosis, tachycardia), tremor, ataxia, many-syllables, hallucinations. The sleep is sharply disturbed. Death occurs with the progression of cardiovascular failure.

Scrapie

Scrapie (scrape) is the prion disease of sheep and goats (scabies), which proceeds with CNS damage, progressive impairment of movements, severe skin itching (scabies), and ends with the death of the animal.

Bovine spongiform encephalopathy

Disease of cattle, characterized by the defeat of the central nervous system, a violation of coordination of movements and the inevitable death of the animal. For the first time the epidemic of the disease broke out in the UK. It was associated with the feeding of animals with meat and bone meal containing pathological prions. The incubation period varies from 1.5 to 15 years. The most infected are the head, spinal cord and eyeballs of animals.

[12], [13], [14], [15], [16], [17], [18]

Laboratory diagnostics of prion diseases

When diagnosed, spongiform changes in the brain, astrocytosis (gliosis), absence of infiltrates of inflammation. The brain is stained with amyloid. In the cerebrospinal fluid, protein markers of prion brain disorders are detected (with the help of ELISA). Genetic analysis of prion gene (PCR) is performed.

Prophylaxis of prion diseases

To neutralize tools and objects of the environment, autoclaving is recommended (at 134 ° C for 18 minutes, at 121 ° C for 1 hour), incineration, additional treatment with bleach and a normal NaCl solution for 1 hour. For non-specific prophylaxis, restrictions are imposed on the use of drugs of animal origin and the production of pituitary hormones of animal origin is prohibited. Limit the transplantation of the dura mater. When working with the dialogical fluids of patients using rubber gloves.