How are infectious prion diseases, like BSE, transmitted?

genegenie · « **on:** 24/08/2003 13:23:48 »

I understand that prion diseases such as Creutzfeldt-Jakob disease can be inherited (due to a mutation in the PrP gene), or acquired by transmission. Does anyone know the proposed mechanism involved in infectious prion diseases ie. how does this variant protein (that contains no genetic material) alter the conformation of endogenous Prp proteins?

NakedScientist · « **Reply #1 on:** 24/08/2003 23:39:03 »

The current theory is that the rogue prion induces a conformational change from an alpha-helical, globular structure to the fibrous beta-pleated architecture characteristic of PrPsc. How it does this is not known. It's a fascinating area...

TNS

bezoar · « **Reply #2 on:** 25/08/2003 05:56:51 »

So the, why does it take so long for the symptoms of the disease to manifest?

Bezoar

genegenie · « **Reply #3 on:** 26/08/2003 09:54:44 »

Apparently it takes a while for the variant proteins to accumulate and cause symptoms. It's amazing, and quite frightening!

bezoar · « **Reply #4 on:** 26/08/2003 15:59:48 »

A while? Twenty years or so? It is amazing and frightening. I was wondering if the body didn't mount some kind of defense and then finally succumb. For something that takes that long, you'd think over a twenty year period, medical science could find some way to interrupt the process.

Bezoar

chris · « **Reply #5 on:** 26/08/2003 19:55:04 »

Well, there are multiple ways to interrupt the process, including antibodies, but they are only any use if given before the person becomes symptomatic. Since the disease follows an accelerating course once neurological symptoms appear, initiating treatment at that stage is a bit like slamming the door once the horse has bolted.

The disease takes a along while to manifest because initially there are very few infections prion particles to initiate the conformational change. However, as more prion proteins are converted to the pathological form the abundance of abnormal prion grows exponentially since, in essence, it catalyses its own production.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

bezoar · « **Reply #6 on:** 27/08/2003 02:26:16 »

So then, is there an antibody to Mad Cow Disease, or I think you all call it BSE? And if so, why not immunize everyone with any possible exposure? Is there any test to detect it before it becomes symptomatic?

Bezoar

genegenie · « **Reply #7 on:** 27/08/2003 06:05:04 »

I wasn't aware that there is treatment available....I'm keen to hear more about that. As far as I know, diagnosis can only be confirmed by autopsy. Build-up of these variant proteins cause plaques that damage the brain.

chris · « **Reply #8 on:** 27/08/2003 11:50:22 »

A novel feature of human BSE is the accumulation (presumably by amplification) of the abnormal prion in peripheral lymphoid tissue PRIOR to the onset of clinical neurological symptoms.

A man from the southwest of the country, by sheer serendipity, underwent appendicectomy a couple of years before being diagnosed with variant CJD (human BSE). Subsequent re-examination of the appendix specimen (which for some reason had been kept, I can't remember why) revealed the hallmark deposits of vCJD. This led to tonsilar biopsy being used in suspected cases.

The only way to diagnose the condition with certainty, during life, is by brain biopsy.

In terms of interventions, researchers have found that blocking certain parts of the immune system (with monoclonal antibodies) can stop prion transmission and amplification, but as I said before, only before it has become clinically manifest.

Chris

This had led to tonsillar biopsy

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

bezoar · « **Reply #9 on:** 27/08/2003 14:50:34 »

And so, what's the rest of the story? Did he receive monoclonal antibodies, and if so, was he cured or was the disease held in check?

Bezoar

Ylide · « **Reply #10 on:** 21/10/2003 10:46:12 »

You'll be happy to know that a researcher at the National Institute of Health has come up with a way of treating prion-infected meats to eliminate the infectivity of said prions. I stumbled across his work in the course of a paper I was writing on the horrible things that are happening to our food supply. This made me feel a bit better...check it out.

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chris · « **Reply #11 on:** 21/10/2003 12:25:02 »

In the above-mentioned (and linked) paper it says

"The scientists found that they were able to retain the basic texture and flavor of the processed meat while reducing the prions to non-infective levels. This may have application in improving the safety of meat products."

...so who tasted the (prion-contaminated)meat before and after treatment to conclude that the processed meat retained "the basic texture and flavor"

! [xx(]

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

tweener · « **Reply #12 on:** 21/10/2003 15:35:24 »

From the sound of what they were testing on (hot dogs), I don't think there would be much flavor or texture worth retaining.

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No words of wisdom here.

Ians Daddy · « **Reply #13 on:** 21/10/2003 20:44:52 »

Agreed.

Ylide · « **Reply #14 on:** 22/10/2003 03:36:09 »

They probably fed it to cows.

In seriousness, they probably tasted the meat before adding the prions, then afterwards checked for prions before tasting it again.

Besides, the proteins in processed meats are pretty much denatured already from the processing, so it's not like pressure and heat are going to make it any worse.

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chris · « **Reply #15 on:** 22/10/2003 11:15:29 »

The point is that prions are clearly not denatured by the kind of processing that is used to prepare 'convenience foods', hence the 120+ cases of human BSE. Prions have been found to be resistant to autoclaving. Indeed contaminated surgical instruments, used previously on individuals who were later found to have been incubating CJD at the time of their brain surgery, have been implicated in the transmission of the disease to other patients.

Furthermore, not long ago a report found that in Germany brain-derived material was still finding its way into German sausages and indeed a friend of mine cut a thin section through such a sausage and stained it with a subtstance that highlights the presence of brain tissue. The test was positive. A paper also appeared in one of the medical journals based on the same test that predicted some types of sausage contained upwards of 15% brain tissue. Germany defended the use of this material by citing the low frequency of BSE in their country. But what they couldn't explain was the huge disparity between the number of cases of BSE you would expect to find in Germany - based upon the number of cows imported from the UK where the frequency of BSE was well established - and the number of cases of BSE that Germany actually reported. Perhaps we can cure BSE... just by shipping cows to Germany

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

Donnah · « **Reply #16 on:** 22/10/2003 15:42:19 »

Chris, so if Prions are resistant to autoclaving, how can surgical instruments be sterilized for protection? Would submerging them in alcohol work?

chris · « **Reply #17 on:** 22/10/2003 21:22:10 »

No. The only way to prevent infection is to throw away the kit.

This has led to the production of single use instruments for certain surgeries and in high risk individuals.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

Ians Daddy · « **Reply #18 on:** 22/10/2003 23:10:27 »

Good God! Does nothing kill these prions? What about freezing or burning? Or nukes? Or bleach? If not, can these things be used in any way constructive, as in an antidote?

bezoar · « **Reply #19 on:** 23/10/2003 00:29:19 »

So Chris, do you eat beef?

Bezoar

chris · « **Reply #20 on:** 23/10/2003 00:51:39 »

Of course. BSE wasn't just in beef. Contamination made it into many household items incuding cosmetics, jelly (what Americans call jello for some reason, probably because they call jam jelly, god knows why), event capsule casings and boot polish (not that many people eat that).

It's also probable that there are some sheep around that are carrying BSE, but because it is indistinguishable from scrapie (in a sheep) which is not perceived to pose a threat to humans, it will be very difficult to track down.

The beef here in the UK is now the safest in the world. I'm not being defensive, merely honest. The safeguards in place here now are very strict. I would much rather eat bef here than in other countries, like Germany and France that denied they had a problem (yet we have statistical and biological evidence that they did) where the safeguards are far fewer. Also worth bearing in mind is that the practices used in the US to rear beef involve exposure to huge doses of hormones and antibiotics. These agents can be transmitted to people consuming dairy and beef products with who knows what impact upon your health.

It always amazes me that Americans are so paranoid about BSE given that there ahve been only about 120 human cases from a total exposed population of millions (most likley the whole beef eating population since the (cow) BSE incidence was exceeding hundres of thousands of cases annually at its peak).

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

tweener · « **Reply #21 on:** 23/10/2003 04:09:09 »

"Good God! Does nothing kill these prions?"

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No words of wisdom here.

tweener · « **Reply #22 on:** 23/10/2003 04:10:43 »

OOPS! I hit the wrong button.

I was going to add to the previous post: Are prions alive? Can they be killed or is the better word "denatured" as you've used, Chris?

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No words of wisdom here.

Ylide · « **Reply #23 on:** 23/10/2003 04:11:42 »

Read the article I linked to. Prions can be denatured. I emailed the researcher that developed the process...they're already working on perfecting it for industry use. They're already lobbying to get FDA regulations mandating the procedure when it is complete.

Personally, I'd rather just see them disallow the use of any animal's brain tissue. Certain things just shouldn't be eaten...brains and genitals for instance.

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genegenie · « **Reply #24 on:** 23/10/2003 05:07:49 »

I've read the article you linked us to cannabinoid, and they don't actually mention denaturing, they use the term 'inactivation'. They also say 'processes such as autoclaving and exposure to strong alkali or bleach are known to kill prions' which as far as I am aware, and Chris has verified, is actually incorrect (just an observation).

My concern about this reported inactivation, is that due to the nature of prions, can they re-activate when conditions are normalised?

tweener · « **Reply #25 on:** 23/10/2003 05:17:31 »

I read the article, but it really only applies to highly processed foods that can't really be hurt by drastic pressure and heat. I don't think a steak would survive in recognizable form. Maybe the process could be adapted though.

Personally, I think brains are very good when they are cooked right. I've never been much on the other end of the animal. [:p]

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No words of wisdom here.

chris · « **Reply #26 on:** 23/10/2003 10:34:05 »

Prion is a termed coined by nobel prize winner Stanley Prusiner and stands for "proteinaceous infective particle" (they switched a couple of lettes around to make it sound better !)

Like enzymes, prions are proteins; they are not alive and cannot be 'killed'. But they can be 'denatured' which means affecting the function of the protein by altering its structure. So when a steak goes in the pan it changes colour, consistency and taste because the proteins it contains permanently change their shape (conformation) in response to the heat of the cooking process.

In the brain the normal prion protein - PrPc - is a globular shape. We don't yet know what it does. But the prion protein can also exist in the form of a flattened fibrous sheet. This is the pathological prion found in scrapie, CJD and BSE. It's referred to as PrPsc and it is very stable and heavily resistant to breakdown enzymically, chemically or with heat and other denaturing agents. It is a problem because this abnormally shaped PrPsc prion protein can, rather like a religious fanatic, go around inflicting itself on normal prions and forcing them to change to the abnormal form too. So in this way, the conversion of the brain's healthy Prpc to PrPsc follows a positive feedback loop because you make more abnormal prions that can then co off an convert more normal prions to the abnormal form. The proces therefore accelerates exponentially. The accumulation of the fibrous prion proteins in the brain produces pathological effects including neuronal cell death and the ensuing dementia.

The evidence for this mechanism is that high levels of the abnormally folded prion protein are found in the brain at death. Mice that have been genetically engineered to lack the normal prion protein can't get the disease. And people who have had brain surgery and been operated on using the same instruments (autoclaved) as someone who has subsequently developed CJD, themselves have gone on to develop CJD.

An interesting, though rare, disease. Your chance of getting it is less than being hit by lightning. The sporadic disease (CJD) crops up with a frequency of about 1 person in a million per year. Hence there are about 60 cases a year in the UK. BSE is much more difficult to predict because all of the victims so far have all shared a gene in common, suggesting that there might be an inherited susceptibility to the disease. Since that gene type is carried by about 20% of the population the future is difficult to predict, although the anticipated number of human cases of BSE has now been hugely down-graded from the terrifying suggestion of "millions" a few years ago to "hundreds" now.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

tweener · « **Reply #27 on:** 23/10/2003 19:26:02 »

Thanks Chris - That is the best description of prions and the various diseases they cause I've yet to hear.

John

bezoar · « **Reply #28 on:** 23/10/2003 21:30:45 »

It would seem that if the abnormal prions can go about coercing the normal ones to go abnormal, then there should be a way to reverse the process, with the normal ones coercing the abnormal ones to go normal. Theoretically, there should be a cure, and maybe it should focus on the resistance and reactivity of the normal prions.

And Chris, do you eat beef?

chris · « **Reply #29 on:** 23/10/2003 22:04:45 »

Bezoar - I did reply to your beef enquiry - see above ! Maybe you've got BSE and forgot [

]

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

genegenie · « **Reply #30 on:** 23/10/2003 22:42:43 »

Great idea bezoar! Perhaps when they figure out how the variant protein alters the normal protein, that could be possible. I suppose I just don't like the idea of inactivation by denaturation, because I think about how easily renaturation occurs in heat denatured DNA. But of course, I'm speaking out of total ignorance [8D]....just my thoughts.[?]

chris · « **Reply #31 on:** 23/10/2003 23:20:49 »

There is a trial on-going with an agent derived from beech chippings called pentosan polysulphate which is administered intraparenchymally - i.e. directly into the brain. In the one case for which there is robust evidence at the moment it seems to have halted the progression of the disease, and produced some modest functional improvements. The agent is believed to hinder the interaction between the abnormal prion and its healthy counterpart.

However it is worth bearing in mind that most of the symptoms of the condition are due to neuronal cell death and so treatment isn't merely a case of removing the pathological deposits.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

bezoar · « **Reply #32 on:** 24/10/2003 13:08:28 »

But isn't the neuronal cell death triggered by the abnormal prion?

chris · « **Reply #33 on:** 24/10/2003 14:27:40 »

Yes, that's what we believe. But my point is that the disease only becomes clinically manifest, and robustly diagnosable, once there has been (considerable) neuronal cell death. To reverse the effects of the clinical syndrome you would need to not only prevent the further accumulation of pathological prions, but also replace the lost cells.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

tweener · « **Reply #34 on:** 24/10/2003 21:43:07 »

Is it possible to replace the lost neuronal cells? If so, how would the new cells be "trained" back into the neural network? I guess what I'm asking is wouldn't the person's memories and skills be lost?

John

chris · « **Reply #35 on:** 25/10/2003 00:05:22 »

That's essentially what people are trying to achieve with stem cell therapy, and neuronal cell grafts taken from foetal tissue. It has shown some promise in patients with Parkinson's Disease, and a trial is underway on Huntington's too.

The reality is that we have no way of knowing how well the new cells integrate into the existing neural network and we have to go on clinical observations only, which could be confounded by a host of factors.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

bezoar · « **Reply #36 on:** 25/10/2003 03:50:51 »

Isn't kuru also a prion disease?

Ylide · « **Reply #37 on:** 25/10/2003 06:56:36 »

Tweener:

Since prions exist in and infect brain matter, your chances of getting one from a steak are pretty slim, even from an infected cow. Processed meats are where the danger lies. And since processed meats can be treated (or will be able to be treated in the near future) I wouldn't worry too much about it.

In the meantime, if you're really worried about it, avoid processed meats, ground beef (unless you pick out the cut of meat and have them grind it right in front of you), and all types of sausages.

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chris · « **Reply #38 on:** 25/10/2003 12:18:29 »

quote:
Originally posted by bezoar

Isn't kuru also a prion disease?

Yes, it was prevalent among the Fore people of New Guinea who practised ritualistic cannibalism which involved eating the brains of dead relatives. Since it was mainly the women that carried out the ritual, the disease predominated amongst the females of the tribe. It disappeared once the practise ceased, indicating the capacity of infectious prions to be transmitted via the oral route.

Kuru actually means "he who trembles" and is a reference to the symptoms experienced by sufferers as the disease becomes manifest and they develop involuntary movements. In some cases these involuntary movements were sufficient to throw some people into their camp fires, though whether they did this partially voluntarily in an attempt to escape the symptoms tey were experiencing, no one knows.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

Ians Daddy · « **Reply #39 on:** 25/10/2003 14:30:48 »

That is an interesting story. You guys never cease to amaze me. That's a good story just in time for Halloween.

bezoar · « **Reply #40 on:** 28/10/2003 03:58:17 »

Oh, I thought you meant the rest of the tribe threw them into the fire. Thought they were just preparing the next meal. I didn't think the symptoms were painful at all. My impression was that it was just a gradual neuro degeneration.

chris · « **Reply #41 on:** 28/10/2003 11:33:22 »

It causes mental anguish owing to the psychiatric changes experienced by some - uncertainty and stress caused by the symptoms. BSE sufferers frequently do complain of pain because the normal systems that relay pain stimuli to the brain and control our perception and conscious experience of pain are disturbed by the disease process.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

puddintame · « **Reply #42 on:** 01/12/2003 23:07:27 »

Topic of "Prions" and "BSE" from October, 2003 talking about other types of contamination that perhaps have occurred or are known to have occurred. My physician had recommended melatonin, but cautioned me to be sure that it was synthetic and not produced from 'cow'. It proved to be a study in 'who knows'. In searching it out I found that most folks having this product on their shelves knew very little about it. Most assured that they stocked nothing but synthetic and this subsequently proved to be true in most cases. Interesting subject matter in this article. The pursuit of how prions function is facinating and we are hearing a lot about the scientists' interest in them these days.

pixcdust · « **Reply #43 on:** 15/01/2004 00:25:15 »

Why doesn't our body break down the BSE? Why are Prions processed by oral ingestion and not destroyed by our enzymes? I need answers, I am a college student and this is for extra credit can someome please help, thanks.

Ylide · « **Reply #44 on:** 15/01/2004 08:21:05 »

You can't uncook a steak. The intermolecular forces that fold proteins together are not quite the same in frequency and structure that bind DNA.

Do they have any idea at all how prions do what they do? Is it a genetic change where RNA is creating proteins incorrectly, or do they alter existing proteins?

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genegenie · « **Reply #45 on:** 23/01/2004 13:00:39 »

They alter existing proteins apparently. There's an intersting article at ...sorry, you cannot view external links. To see them, please REGISTER or LOGIN which also talks about genetic susceptibility to prion disease. Nasty stuff!!

Big_Jules · « **Reply #46 on:** 09/04/2004 02:56:02 »

To add another layer to this discussion, there is variation in the sequence of bases in the gene and hence the sequence of amino acids (building blocks) in normal prion protein among any animal species, including us. Such differences also confer a greater disposition to heritable neurodegenerative diseases such as conventional CJD. It appears that certain of these variations make the normal prion protein more or less susceptible to confirmational change induced by the 'rogue' prion protein. Several of these sequences have been identified. Presumably, interaction between key amino acid sequences in the rogue and normal proteins enact the conformational change. As Chris has stated, the beta-sheet conformation appears to be highly resistant to enzymatic digestion, so that enzymatic digestion, specially within neural tissue, is unlikely. With respect to antibodies, one would imagine that the indigenous protein, while changed in shape, would still be recognised as 'self' and not susceptible to immune attack.

chris · « **Reply #47 on:** 09/04/2004 06:07:20 »

The point is Jules, that since the abnormal form of the prion protein seems to be heavily resistant to digestion with proteases, it is hard to envisage how an antigen presenting cell could chew it up and present it effectively in the first place, in order to initiate an immune response. This may be why there is so little immune response to the accumulating pathological prions.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

Big_Jules · « **Reply #48 on:** 09/04/2004 02:56:02 »

To add another layer to this discussion, there is variation in the sequence of bases in the gene and hence the sequence of amino acids (building blocks) in normal prion protein among any animal species, including us. Such differences also confer a greater disposition to heritable neurodegenerative diseases such as conventional CJD. It appears that certain of these variations make the normal prion protein more or less susceptible to confirmational change induced by the 'rogue' prion protein. Several of these sequences have been identified. Presumably, interaction between key amino acid sequences in the rogue and normal proteins enact the conformational change. As Chris has stated, the beta-sheet conformation appears to be highly resistant to enzymatic digestion, so that enzymatic digestion, specially within neural tissue, is unlikely. With respect to antibodies, one would imagine that the indigenous protein, while changed in shape, would still be recognised as 'self' and not susceptible to immune attack.

chris · « **Reply #49 on:** 09/04/2004 06:07:20 »

The point is Jules, that since the abnormal form of the prion protein seems to be heavily resistant to digestion with proteases, it is hard to envisage how an antigen presenting cell could chew it up and present it effectively in the first place, in order to initiate an immune response. This may be why there is so little immune response to the accumulating pathological prions.

Chris

"I never forget a face, but in your case I'll make an exception"
- Groucho Marx

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How are infectious prion diseases, like BSE, transmitted?

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