Prion diseases operate differently than any other class of disease we are currently aware of. It is reliant on mutated forms of a common mammalian protein known as prion protein (PrPc). PrPc is highly homologous among mammals. In humans this protein is expressed in the central nervous system as well as in leukocytes and the gut. Common diseases known to be prion in nature include kuru, scrapie, Creutzfeldt–Jacob disease (CJD), Bovine Spongiform Encephalopathy (BSE/”mad cow”), and Gerstmann Straussler Scheinker (GSS) disease. Prion diseases are unique also in that there are three known ways for one to contract them: infectious, inherited, and sporadic.

A modified prion protein (PrPsc) has properties very different from those of the unmodified PrPc. PrPsc is highly resistant to the enzymatic degradation of the ubiquitin-proteasome system causing them to build up. This is a result of the changes in the secondary structure of PrPc, that is PrPsc has many areas of alpha helixes converted to beta sheets. These proteins build up in the brain causing cell death.

When a PrPsc molecule in introduced into a healthy animal it causes conformational changes in the healthy PrPc forms of the protein. This process is known as “Pruisner’s Theory”. This theory is evidenced by the tendency of aggregates to resemble the primary structure of the PrPc of a particular organism.

Recent studies have hinted that PrPsc aggregates are not necessary for prion-related neurotoxicity. If proteins are non-functional they are tagged by ubiquitin and degraded in a proteasome. This goes for PrPc as well. It has been discovered that if the ubiquitin-proteasome is inhibited, misfolded PrPc will build up in the cytosol and cause classic prion-related neurotoxicity. These PrPc proteins will aggregate in the cytosol and cannot be cleared by reinitializing the ubiquitin-proteasome system.

There are several findings in mouse studies that must be taken into consideration when thinking about the role of PrPsc in disease. It cannot cause disease when no PrPc is present. In a study mice with out the PrP gene (prpn) the PrPsc was unable to cause disease. Mice with truncated prpn producing non-functional PrP have high levels of cytosolic PrP and have massive neuronal loss. Older mice can spontaneously develop these symptoms, presumably sporadically. If PrPc production is inhibited in early PrPsc infection symptoms will not develop. The concentration of PrPsc does not seem to have an effect on the severity of the disease.

The new research raises many questions about the role of PrPc in relation to PrPsc exposure. It seems clear that PrPsc converts PrPc to the highly toxic form. However, it also seems clear that PrP itself can contribute to disease if the ubiquitin-proteasome system is not working properly.

It is put forth by researchers that the introduction of PrPsc may not be the determining factor in the development of neurodegenerative symptoms. This could be caused by a defect in the processing or metabolism of PrPc, or in the prpn gene itself. They state that an exogeneous form of PrPsc may initiate the events leading to the build up of PrPc in the cytosol and that this PrPc may fuel the further accumulation of PrPsc aggregates. This process may actually explain infectious, inherited, and sporadic prion disorders.

This article is a summary of recent reports released by the the World Health Organization. I hope to characterize the WHO proposed framework for preventing chronic disease.

With over 58 million deaths each year chronic disease will account for over 35 million of them. These include heart disease, stroke, cancer, and other chronic diseases. 15 million of these deaths occur in people under the age of 70. Contrary to popular belief, these are not “diseases of affluence”. Four out of five deaths from chronic disease are seen in low to middle income nations. These figures are increasing, which is especially alarming considering much of it is avoidable. Over 80% of heart disease, stroke, and diabetes as well as 40% of cancer could be avoided through life style modifications. In many afflicted nations medical treatment is spotty at best and medications are hard to come by. The goal of a WHO initiative is to reduce deaths from chronic disease by 2% each year.

In fact physical exercise, avoidance of tobacco, and a reasonable diet are the most important first steps in reducing the death rate. This may seem a daunting task for many nations, but the WHO has developed a stepwise plan of action. There are three main planning steps and three main implementation steps.

In the planning steps the first part is the acceptance of this framework by the national government. Without this support the effort will inevitably fail. Indonesia’s attempt at implementation is evidence of this. Chronic disease rates doubled there between 1981 and 2001 but only when all government groups collaborated were they able to get a plan in place. The next step is to adopt a plan for combating chronic disease that will take action in the next 5-10 years. The final planning step is to evaluate which steps will provide the most benefit and where. Also, determining what groups will be responsible for what steps.

This implementation steps are often known as core, expanded, and desirable. It is up to each nation to decide what issues they want to focus on (the core). It is important that they not overextend themselves in the expansion phase. It is bet that they do fewer things well than many things poorly. Finally, those in charge must assure that these reforms fit with those already in place.

It is nearly impossible for a single group to institute a national framework in this way. It requires the cooperation of health-based and non-health sectors to function. Indeed, this process requires the involvement of the civil, private and international sectors. Several nations including Tonga, Vietnam, and the Philippines have used this framework to institute programs to combat chronic disease.

All nations could benefit from this process. If we were able to decrease the incidences of death from chronic disease by 2% a year 36 million lives would have been saved by 2015. It is a mater of fact that we must support these programs, especially in low-income nations. Many of these diseases are endemic in these areas and could be corrected with a small amount of political attention. It would not take decades to see a change as some would believe. Many heath benefits can be seen very quickly; for example, tobacco-free policies. People will eventually die of something but no one deserves to go through life with chronic disease.

Firstly, let me thank the agricultural biotech groups and newsletters that picked up my last post about GM crops. It’s nice you enjoyed it enough to distribute it, and for the record I have no qualms about it. This post will probably less divisive (read: popular) though.  I encourage people to comment, even argue with me if they want.  But seriously, I don’t speak German.  Certain individuals (you know who you are) obviously understand English well enough to be pissed off.  If you want to tell me off, do it in English.

Francisella tularensis is an intracellular pathogen that is a potential bioweapon. It causes the disease tularemia; there is no vaccine for Francisella. It infects and replicates in macrophages by a novel mechanism that sets it apart from other intracellular pathogens. It is capable of interfering with the fusion of the Francisella-containing phagosome (FCP) with the lysosome, thereby creating a niche for itself. This organism diverges from the accepted mechanisms of other intracellular organisms. There are four different subspecies of F. tularensis: tularensis, holarctica, mediasiatica and novicida. F. t. tularensis is the most common pathogen associated with humans.

Foreign particles are taken up by macrophages and degraded in low pH vacuoles called lysosomes. As with most intracellular pathogens Francisella tularensis must prevent the phagosome it is contained in from merging with the lysosomal vacuole. A phagosome is simply the vacuole that a bacterium is contained in after it is internalized. Different intracellular organisms have different methods of disrupting the fusion of the phagosome and lysosome. The more common method used by Legionella and Chlamydia involves exporting bacterial effectors to the cytosolic surface of the phagosome. This prevents it from merging with a lysosome and does not interfere with the biochemical processes of the cell. The second and less common method is for the pathogen to export effector molecules to the cytosol where they interfere with all endocytic vesicles.

F. tularensis has decidedly different properties and thus is unique. It is taken up by what appears to be a microtubule dependent mechanism. The macrophage’s compliment receptor may be involved with internalizing the bacterium. Interestingly, this same novel mechanism is seen even with heat or formalin killed F. tularensis. The phagosome is remodeled quickly after infection. The bacterium has an unknown mechanism for keeping the phagosome from becoming too acidic. By 3-4 hours after infection the membrane of the phagosome will be weakened and breaks down releasing bacteria into the cytosol at about the 8 hour mark. It is here that they will replicate. However, the same killed bacteria from above have been found to be degraded in lysosomes just as any other particle would be.

Despite how quickly F. tularesis replicates it cannot propagate in activated macrophages. Though, no known pathogen can. The mechanism for this varies from one pathogen to another. In this case it seems to be that the phagosome does fuse with a lysosomal vacuole. In addition to this the bacterium seems to be unable to affect the phagosome to break it down.

Recently new details of the pathogenicity have been discovered. A pathogenicity island (FPI) has been identified in several subtypes of Francisella. Many of the genes in the FPI are integral to the intracellular nature of F. tularensis. It seems likely that these gene products are needed for escape from the phagosome. This would explain why killed bacteria are degraded but can still be internalized normally.

This is a very interesting bacterium with many unknowns. With such a pathogenic organism it is important threat we unravel these mysteries as quickly as possible. The effects of infection can be truly horrible so we must not allow ignorance to be our downfall.