by Brooke Napier

After talking with my lab mate about which is scarier, black holes or 0 degrees Kelvin, we started thinking about what is the scariest topic in microbiology.

The ebola outbreaks in Uganda? Close, but not the winner.

The Winner: Prions - unpredictable, infectious, non-viral, non-bacterial, misfolded proteins. There are no vaccines, no known cures, no understanding of how it infects, let alone how to stop it.

Prions are the infectious agent responsible for the damaging neurodegenerative diseases Creutzfeldt-Jakob disease (in humans) and bovine spongiform encephalopathy (BSE, also known as “mad cow disease”).

When prions enter the body they act as a template to guide misfolding of more proteins into prions. Then these newly misfolded proteins can go on and act as misfolding templates for more proteins, and so on. This chain reaction causes characteristic “holes” in affected tissues (or a “spongy” look) due to the aggregation of prions in the central nervous system forming plaques (known as amyloid plaques).

Immunostaining for amyloid plaques (black tangles) spread throughout neurons.

Have any more questions? Yeah, us too.

What is this infectious agent?

The protein PrP, found throughout central nervous system, causes all known prion-associated diseases. The properly folded PrP protein is called PrPC (for Common or Cellular) and the misfolded PrP protein is called PrPSc (for Scrapie, after one of the first diseases linked to prions).

There is no genetic information within these infectious agents. Additionally, there is currently no known structure for these isoforms – crystallographers get on it!

How can misfolded proteins infect humans?

Generally, we don’t understand the reasons why human prion diseases occur, however it is known that there can be genetic predispositions for these diseases. PRNP is the gene that encodes the PrP protein, and over 20 mutations in this prion gene may lead to inherited prion disease. Prion diseases are also contracted.

We know they enter through extra-neural pathways, circumventing the innate and adaptative immune system and traveling across the blood-brain barrier – but how?

Oral Route:

Due to interesting cultural practices of the Fore people in Northern Papua New Guinea involving cannibalism we know that oral uptake is an infectious route of transmission. Kuru, a human prion disease transmitted through cannibalism, is seen at extraordinary high rates in these people.

Fore People.

Additionally, “mad cow disease” has killed more than 280,000 cattle worldwide by feeding “prion-infected foodstuff” to cattle, or forced cannibalism of cow brain, spinal cord, and nerves. Creutzfelt-Jakob Disease (vCJD), in humans, can also be caused by consumption of prion-contaminated beef products (over 200 cases to date – these data also bring into light that transmission of prions can jump species = SCARY).

Hospital-related infections:

There are reports of transmission of vCJD by blood transfusions and through exchange of human pituitary hormones. The latter was the cause of a very large prion-related incident, and is due to the use of growth hormone (used to treat dwarfism) and fertility hormones for hormone-treatment therapy.

These hormones are cultivated from human cadaver pituitary extracts – some of these cadavers were CJD-affected and some of the disease might have been caused by brain-tissue contamination of pituitary extracts. Over 160 prion-associated deaths occurred due to these treatments.

Additionally, transmission of prions directly into the brain (or intracerebral administration) can occur via neurosurgery and human cadaver dura matter grafts. A well-documented case of intracerebral prion transmission was in Zürich during the 1970’s when electrodes were used for electroencephalographic (EEG) recordings in a CJD patient and reused after sterlization, effective against bacteria and viruses but ineffective against prions.

Aerosols:

Luckily, prions are not usually considered airborne (like influenza); however it has been recently found that prions can be transmitted to mice through aerosols. This again frightens me beyond belief.

But, moving on…

After transmission, how do prions cause damage to the CNS?

They must first be delivered to the CNS.

Before prions reach the nervous system, they frequently colonize with follicular dendritic cells (FDCs) within lymph nodes. FDCs are considered to be the main sites of prion accumulation and can develop high prion concentrations within the lymph nodes; however, there is data suggesting that cells other than FDCs are able to replicate prions, but have not yet been identified.

After accumulation in the lymph nodes, prions can invade the nervous system through the sympathetic (responsible for the fight-or-flight response) and parasympathetic (responsible for the rest-and-digest response) nervous system. These pathways have not fully been understood, however researchers have identified that innervation of the sympathetic nervous system can accelerate prion pathogenesis, or spread. Additionally, neural invasion depends on the distance between the FDCs and the nerves surrounding the FDCs.

Intriguing! And hopefully we’ll know more soon…

With all this information I’m feeling helpless against prions, hopefully there is some way we can prevent the spread of prions – which leads us to our next question:

Do we have any natural defense again prions?

Good news, the half-life of PrPSc, or the infectious prion in question, is 2 days. Not long for an infectious agent considering bacteria and viruses can persist chronically for decades.

Our problem here is we need to know what cells contribute to the clearing of prions within those short days. Identifying these cells will be key in finding how to clear prions more efficiently.

We have one lead, new evidence has shown that microglia might be the primary prion-cleaner-uper. Microglia are glial cells in the brain, and they are basically the first line of defense in the nervous system, acting like a macrophage immune cell by eating and destroying any foreign particles in the CNS. They are generally in charge of clearing CNS debris or infectious agents in the brain, but how can microglia identify prions as infectious material (because prions are just proteins!)?

This question is being currently investigated and there are small clues that particular mediators may be responsible… more on this when there is more research done!

Do we have any chance of fighting this infectious agent?

Ok, so we know now that some how if we find the cellular agent in microglia cells that is responsible for clearance of prions we MIGHT be ok… that’s a lot of uncertainty.

We know that organisms that do not produce PrPC , the regular PrP protein, are the only known organisms resistant to prion-related diseases (which makes sense, since you need the protein in the first place in order to misfold it). Therefore, industry has focused on breeding PrPC-deficient farm animals, and has succeeded in making goats and cattle – but my question is, are they still tasty?

I’m not entirely sure where the next leg of research will take our knowledge on this topic, but I will be eagerly awaiting the results.

Aguzzi A, & Zhu C (2012). Five questions on prion diseases. PLoS pathogens, 8 (5) PMID: 22570608