#openaccess: Exploitive prions versus your innocent immune system

Prion protein in red on dendritic cell beside neuron (green)

This blog focuses on trying to understand how viruses cause disease in their hosts - whether they be single cells or us, humans. Attempting to do so means that we must look at how viruses enter these hosts, survive within the hostile environment that is another organism and eventually make their way on to infect the next one. One thing this blog doesn't do, is look at how other kinds of pathogens complete this complex life cycle.

I'm going to change that now.

I'm going to take a look at prions - the dangerous proteins behind the fatal brain disorders such as: Kuru, mad-cow disease and scrapie, also known as 'Transmissible spongiform encephalopathies' or TSE's.

A paper published last week in PLoS Pathogens really highlights an issue that comes up a fair bit in this blog, that is: how pathogens - in this case prion proteins - exploit your immune system to promote their own survival. And in particular, how these molecular parasites make use of one cell: the dendritic cell. This work comes from the Medical Research Council's Prion Unit in the UK.


Now I'm going to tell you a secret: our immune system - built up of a dozen different cell types and tissues, hundreds of genes and proteins and featuring a multitude of structural defences that make a castle look weak - isn't perfect. You may be one of those people that 'never gets sick' - and that's great - but if you stand back and take a good look at it, there are some pretty substantial weaknesses found among all those cells and sadly. This isn't something that other organisms have failed to notice.

A dendritic cell in blue doing what it does best - interacting with another immune cell (T cell in yellow).

Dendritic cells, named for their recognisiable 'tree-(or dendrite)-like' structure, form an extremely important part of your vertebrate immune system: they physically and functionally blur the lines between the two 'arms' of immunity; the innate and the adaptive. The major feature that allows these cells to be so effective at doing this job is their location at sites in your body that are in continuous contact with the outside environment, your mucosal surfaces: skin, gut, lungs and genitals.

Here they can continuously sample the outside world and report back to your immune system allowing a response to be mounted. This communication between dendritic cells and your immune system occurs in tissues and organs like lymph nodes or your spleen and here they kick your T and B cells into action. Dendritic cells are the text-book example of 'antigen-presenting cells' but what if that antigen is an infectious - and deadly - prion?

In mammals - like humans, sheep and cows - prions are very dangerous proteins (although in yeast they have a positive effect on survival). They physically interact with a normal, healthy protein inside our cells (aptly named: cellular prion protein) and cause them to structurally rearrange themselves in a way which resembles the initial dangerous protein.

That is: they are self-replicating proteins.

While viruses are made up nucleic acid (DNA or RNA) in a protein shell, these prions skip out the DNA and use their protein structure to encode heritable information.

Heritable information which can be fatal.

But when these prion molecules interact with your cells and replicate themselves they begin to clog up the normal functioning of the infected cell and this is what triggers the cell to die. This is the precise mechanism by how these proteins cause your brain cells to disappear and for symptoms like mad-cow disease to form. The animals brain cells are beng clogged up by prions and are dying.

But we have one problem, we aren't completely sure how these self-replicating proteins can physically get around the body from their portal of entry. One thing that we can agree on is that we first come into contact with the prion protein on what are known as mucosal surfaces. Surfaces like your upper respiratory tract or gastrointestinal tract.

For example, when humans ate prion-infected brain material during cannibalism they would expose themselves to infectious prions in their gut. Here specialised cells lining these tracts traffic the protein to local immune cells which allowed the protein to replicate itself in those cells. It is thought that prions require this initial phase of replication to allow itself access to your brain. Although they are known to head directly into closeby by neurons.

Prions can be thought of being quite similar to viruses in that they require a living cell to make more copies of themselves. We can thus ask the question: in our body, what cells are important for prion entry into our body, replication and spread to sites like your nervous system.

This PLoS Pathogens paper uncovered a previously unrecognised mechanism that may explain how these proteins move around the body. They show for the first time that two kinds of cells (the plasmacytoid dendritic cell and the natural killer cell) are associated with very high levels of the infectious protein while inside your spleen - which is itself a special kind of immune organ. These immune cells are being shown to play a role that is in fact doing the opposite of what you might think they should do. They are actually promoting the survival and propagation of these prions throughout an infected organism as the worrying thing about these cells is that they are very good at moving from organ to organ in your body and can even get inside your brain. And under certain conditions they could actually release packages of the prions into the surrounding environment.

Prion-filled packages released from infected cells

This work suggests a tantalising explanation as to how prions cause life-threatening disease in their mammal hosts. And could even afford us a chance to prevent the progression of the illness following exposure. Future work should focus on replicating this work a better model than what was done (was done in a mouse) and it should also be under more 'natural' conditions, i.e they should feed the prions to the animals and not inject it. A better understanding will also come from tracking these moving cells at early stages of infection and should also show movement of prion-rich cells into the brain.

Castro-Seoane, R., Hummerich, H., Sweeting, T., Tattum, M., Linehan, J., Fernandez de Marco, M., Brandner, S., Collinge, J., & Klöhn, P. (2012). Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection PLoS Pathogens, 8 (2) DOI: 10.1371/journal.ppat.1002538


Want to know more about dendritic cells and infections?

• How do viruses influence dendritic cell the dendritic cell response? HIV story.
• The influenza story.
• How HIV uses dendritic cells move from one cell to another - AND avoid antivirals
• The story of measles: entry, dendritic cells and exit from the body.