Chapter 31: Unconventional Infectious Agents

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Welcome back to the Deep Dive.

We've got a stack of research on the desk today that, and I really don't say this lightly, it challenges pretty much every rule we learned in high school I mean, usually when we talk about things that make us sick, the, you know, the bad guys of microbiology, we have a standard lineup.

Right.

The usual suspects, bacteria, parasites, fungi.

Or at the very least viruses.

And all of those things, even the viruses, they have a plan.

They have a blueprint.

A genetic instruction manual, DNA or RNA.

Exactly.

It tells them how to replicate, how to take over a host.

But today,

today we're, we're kind of throwing that manual into the shredder.

Yeah, yeah.

We are looking at a killer that is just a molecule, a single rogue molecule.

No DNA.

No RNA.

Just a protein that went bad.

It's one of the most unsettling discoveries in modern medicine, really.

We are digging into Lippincott Illustrated Reviews, microbiology, specifically chapter 31.

This is the chapter on unconventional infectious agents.

And our mission today is to break down the science of prions.

Prions and the diseases they cause, which are collectively known as transmissible spongiform encephalopathies or TSEs.

Okay.

That is a massive mouthful.

It is.

It is.

But if we break it down, it tells you exactly what's happening.

But before we even get to the prion part, the what, we really have to understand the TSE part, the what happens.

And the text makes a really crucial distinction right at the start.

It's between an encephalopathy and encephalitis.

Okay.

Let's unpack this.

They sound very similar.

Encephalitis is something I think most people have heard of.

Right.

Swelling of the brain, usually from a virus.

Precisely.

Encephalitis is an inflammatory condition.

If you have, say, a viral encephalitis from West Nile or herpes, your immune system goes to war.

Right.

You have white blood cells rushing into the brain tissue to fate the invader.

It's hot.

It's swollen.

You get a fever.

It's a battlefield.

So encephalitis equals inflammation,

a war zone.

Exactly.

Now TSEs, these prion diseases, are completely different.

They are silent destroyers.

There is a distinct absence of inflammatory signs.

No fever.

No white blood cells rushing in.

The body, it doesn't even seem to realize it's under attack.

So what's happening to the brain if it's not inflammation?

The brain tissue develops spongiform vacillation.

Which basically means it turns into a sponge.

Literally.

If you look at the brain tissue under a microscope, the gray matter is just full of holes where the neurons used to be.

The structure just collapses and you're left with this Swiss cheese appearance.

That's the spongiform part of the name.

And the scary part is, because there's no inflammation, it happens quietly until the damage is catastrophic.

That is terrifying.

Okay.

So we have a brain turning into a spun without the immune system even noticing.

So let's look at the culprit, segment one.

What is a prion?

So in the text, we have figure 31 .1.

It classifies all the infectious agents.

You have your big circle for bacteria, another for fungi, protozoa, viruses.

And then what?

And then, sitting all by itself in the corner, are the unconventional agents.

And the text says scientists were astonished when they first identified this.

You were.

Because when they purified the infectious agent causing Scrapey, that's disease in sheep, they kept looking for the genetic material.

But DNA or RNA?

Right.

They treated it with UV light, which destroys DNA.

They boiled it.

They used chemicals that break down nucleic acids.

And the agent was still infectious.

It survived things that should kill any living organism.

Eventually, they realized why.

There was no DNA to kill.

The infectivity was associated with a single protein species.

They called it the prion protein or PRP.

So just to be crystal clear for everyone listening, this thing has no genetic core, no nucleus.

None.

It's a protein shell with nothing inside.

It challenges the very definition of what an infectious agent can even be.

The text mentions figure 31 .2, an electron micrograph.

Now, if I'm looking at a virus under a microscope, I usually see little geometric shapes, right?

Like spheres or rods.

Right.

Viruses have capsids.

They have a distinct geometry.

But here, if you look at that figure, you don't see particles.

What do you see?

You see fibrils.

These are fibrillar proteins accumulating in the brain.

They look like little threads or tangled fibers all clumped together.

These are what we call amyloid -like fibrils.

Okay.

So we have a protein thread that kills, but here's where it gets really interesting.

The text says this protein isn't some alien invader.

It's already inside us.

This is the plot twist.

Yes.

We all have the prion protein inside us right now.

It's encoded on our own chromosome 20.

Wait, I have it.

You have it.

We do.

But we have the good version.

This is the old Dr.

Jekyll and Mr.

Hyde scenario the text lays out.

Okay.

Lay it out for us.

What's the difference between the good protein and the bad one?

So there are two forms.

First, you have PRPC.

The little C stands for cellular.

This is the normal non -infectious form.

It sits on the surface of your neurons and glial cells.

It's found in all mammals.

And it's behaving itself.

Perfectly.

Structurally, it's made of a lot of what we call alpha helices.

If you remember your biochemistry, you can think of alpha helices as these nice spiral staircases.

They're flexible and they can be broken down by the cell when they get old.

Spiral staircases.

Flexible.

Safe.

That's Dr.

Jekyll.

Then you have the mutated form.

PRPSC.

The CSE stands for scrapie after the sheep disease.

This is the infectious one.

Now, here's the kicker.

What's that?

It is the exact same amino acid sequence as the normal one.

It's same ingredients.

Same ingredients, same gene sequence.

But the shape is different.

How different?

Instead of those nice spiral alpha helices, the infectious form replaces them with beta sheets.

Think of flat, jagged, rigid sheets of paper.

So it's purely a shape shifting problem.

It's like an umbrella suddenly snapping inside out.

That's a great analogy.

And that shape changes everything because those beta sheets make the protein incredibly tough.

Tough how?

The normal alpha helix form can be broken down by enzymes, proteases, when the cell needs to clean house.

The beta sheet form.

It's like a rock.

It is resistant to proteolytic degradation.

It jams up the garbage disposal?

Effectively.

So instead of being recycled, it forms these insoluble aggregates, those fibrils we saw in the image, and they just accumulate until they clog up the brain cells and kill them.

Okay.

But here's the question that I think stumps everyone.

If it has no DNA, how does it reproduce?

How does one bad protein become a brain full of them?

This brings us to figure 31 .3 in the text, which outlines the whole mechanism.

It isn't reproduction in the biological sense.

It's conversion.

It's a chain reaction.

Walk us through it.

Okay, step one.

An infectious PRP molecule, the beta sheet, one enters the body, or maybe arises spontaneously.

Yeah.

It then bumps into a normal PRP molecule, the alpha helix one just sitting on your neuron.

A bad influence.

The ultimate bad influence.

When they interact, the bad protein acts as a template.

It physically forces the normal protein to unfold and refold into the infectious shape.

It recruits it.

It converts it.

So now you don't have one bad and one good.

You have two bad molecules.

And then?

Then those two separate.

Okay.

And they go find two more normal molecules.

Now you have four.

Then eight, then 16.

It's exponential.

It's a cascade.

And since we all have a ready supply of the normal protein on our neurons, there's plenty of fuel for this fire.

So it doesn't need its own DNA.

It just corrupts our own supply.

That's it.

It's horribly efficient.

It uses our own biology against us.

Fascinating and terrifying.

Okay, so we know what it is.

We know how it works.

How do you get it?

This brings us to the epidemiology segment.

Right.

Historically, this all started in animals.

We mentioned scrapie and sheep.

But the one most people remember, the one that made all the is BSE.

Mad cow disease.

Bovine spongiform encephalopathy.

This arose in British cattle in the 80s and 90s.

And the cause was chillingly simple.

They were feeding cattle meat and bone meal that contained rendered parts from diseased sheep and other cattle.

So forced cannibalism.

Essentially, yes.

And that recycling of the protein allowed the agent to just amplify throughout the food supply.

The big question at the time was, you know, can this jump to humans?

The answer was yes.

Yes.

We call it variant CJD or VCJD.

This is when humans get it from eating infected beef.

And what's distinct here, according to the text, is the age of the patients.

Classic prion diseases usually hit older people in their 60s.

But not this one.

But VCJD was hitting young people, teenagers, people in their 20s.

An incubation period.

The text says four to 40 years.

That's the part that keeps epidemiologists up at night.

Yeah.

You could be exposed today and not show symptoms for decades.

We don't really know the full scale of the potential epidemic because of that massive lag time.

No, speaking of transmission, there is a historical example in the text that is, well, it's intense.

Kuru.

Ah yes, Kuru.

Found in the four people of Papua New Guinea.

It was a neurological disease that primarily affected women and children.

And it turned out to be transmitted through.

Ritualistic cannibalism.

To honor the dead, it was a funeral rite who consumed the brain tissue of deceased family members.

And the brain is where the prions concentrate.

Exactly.

So the infection rate was incredibly high.

The good news is, since that practice stopped back in the late 50s, the disease has essentially disappeared.

So eating brains is a bad idea.

But there's another way to get it that's even more tragic because it happened in hospitals.

Iatrogenic CJD.

Doctor caused transmission.

Unintentional, of course.

But the text lists specific examples.

Contaminated corneal transplants, brain electrodes that weren't cleaned properly.

Because normal cleaning doesn't kill prions.

Right.

And a big one was human growth hormone.

Before they could make it synthetically, they used to extract it from the pituitary glands of thousands of pooled cadavers.

So if just one of those cadavers had CJD?

The whole batch was contaminated.

It's tragic.

Wow.

But putting aside the beef and the medical accidents, most cases just happen, right?

The vast majority, 85 % are what we call sporadic CJD.

About one to two per million people.

We don't know why.

Maybe a random protein just flips shape on its own.

And there's a genetic component too.

About 15 % are inherited.

You can get a mutation in the PRP gene that just makes your normal protein a bit unstable.

More prone to collapsing spontaneously.

I want to touch on one detail.

The knockout mice.

This seems like the smoking gun for the whole theory.

Yes.

This is the proof of the mechanism.

Scientists bred mice that didn't have the PRP gene.

They were knocked out.

And what happened when they injected them with the disease?

Nothing.

They were completely immune.

Because there was no normal protein to corrupt.

Exactly.

You can't have a chain reaction if you don't have the fuel.

It proved the host's own protein is essential for the disease to progress.

That is wild.

Okay.

Let's talk about what this actually looks like in a patient.

We have a few acronyms here.

CJD, GSS, FI.

These are the different phenotypes, the different ways the disease can present.

Okay.

Start with CJD, Creutzfeldt -Jakob disease.

CJD is the most common.

It's characterized by a rapidly progressive dementia.

We're talking behavioral changes, memory loss, confusion, muscle jerk.

And rapid is the key word here.

Absolutely.

Death usually occurs within one year of symptoms.

It's devastatingly fast.

Much faster than Alzheimer's.

Exactly.

Then you have GSS -Gershman -Straussler syndrome.

This one affects the cerebellum more.

So the primary symptom isn't dementia at first.

It's ataxia.

Loss of coordination.

Right.

Stumbling, trouble walking.

And it's a slower progression, usually two to six years.

And the third one, this one sounds like a horror movie, fatal familial insomnia.

FFI.

It's exactly what it sounds like.

It affects the thalamus, which regulates sleep.

The patient develops an uncontrollable insomnia.

They physically cannot sleep.

Wow.

Which leads to hallucinations, delirium, and then death, usually within about a year.

And these all share that same underlying pathology, the amyloid plaques.

Yes.

And the text makes an important note here, comparing these to Alzheimer's plaques.

Alzheimer's also has amyloid plaques.

But, and this is high yield for any students listening, there are totally different proteins.

Different proteins, different genes.

Correct.

So they are distinct diseases.

Got it.

Now let's zoom out.

Figure 31 .4 in the text is a comparison table between prions and conventional agents.

This feels like the summary you want to memorize.

This is the what makes prions specialist for sure.

Let's hit the similarities first.

Not many, right?

Well, they're both transmissible.

They both multiply in the host.

Okay.

And they both have different strains.

Okay.

Standard stuff.

Now for the differences, this is the key part.

The differences explain why this is so dangerous.

Number one, resistance.

Prions are incredibly tough.

Resistant to what?

Almost everything.

UV light and x -rays.

Useless.

Because they target DNA.

And prions have no DNA.

Formaldehyde, alcohol,

doesn't touch them.

Difference number two.

The immune response.

We touched on this, but it's critical.

In a viral infection, you see antibodies, you see inflammation.

In a prion disease,

silence.

Nothing.

No humoral immune response, no inflammatory response.

Because the protein looks like self.

And finally, visibility.

Right.

You don't see virus particles under the microscope.

Yeah.

Just those fibrils.

This leads us right into diagnosis and treatment.

If the body doesn't react, and it's hard to see, how do you diagnose it?

Well, the definitive diagnosis is a post -mortem brain autopsy.

That's not very helpful for the living patient.

No.

While the patient is alive, it's very difficult.

Routine labs are usually normal.

The text notes that with VCJD, the mad cow type, you can sometimes find the protein in tonsils.

But often, it's a clinical diagnosis based on that rabid dementia and just ruling everything else out.

And if you do diagnose it, what's the treatment?

The text is blunt.

TSEs are invariably fatal.

There is no treatment.

That is heavy.

It is.

Which emphasizes why prevention and infection control are so critical.

But even that is hard because of their resistance.

The disinfection section.

You can't just wipe down surgical tools with Lysol.

Not even close.

Standard hospital cleaning doesn't work.

The protocol is intense.

You need to autoclave that steam sterilization at 132 degrees Celsius, which is higher than normal.

And you also need to immerse the instruments in undiluted bleach or sodium hydroxide.

You essentially have to boil it in bleach.

Pretty much.

That beta sheet structure is just incredibly stable.

All right.

Let's apply all this.

The text gives us a study question.

I'm going to read the scenario and you walk us through the logic.

Let's do it.

Scenario.

A patient has variant CJD from eating contaminated beef.

What will you find?

Option A, antibodies against bovine antigens.

B, DNA copies of the bovine agent.

C, T cells attacking the brain.

D, amyloid deposits made of bovine amino acid sequences.

Or E, lack of any bovine specific protein or nucleic acid and a lack of immune response.

Okay.

So this question is designed to trap you if you're thinking like a virologist.

So let's rule them out.

Why not A or C, antibodies or T cells?

Because there's no inflammation.

The body does not mount an immune response.

So A and C are out immediately.

Why not B, DNA copies?

Friens have no DNA.

B is out.

Now D is the tricky one.

Amyloid deposits made of bovine sequences.

The patient ate a cow.

Why isn't the cow protein there?

Because the cow prion didn't multiply itself.

It just acted as a template.

It converted the human's own protein.

So the amyloid plaques are made of the patient's human protein just folded wrong.

Which leaves us with E.

E, a lack of bovine specific stuff and a lack of immune response.

It's a disease of the host's own making just triggered by a catalyst.

It really is a unique biological phenomenon.

It forces you to think what infection even means.

It does.

It blurs the line between infectious disease and genetic disease.

It's a category all its own.

So let's wrap this up.

What are the big takeaways from chapter 31?

Okay.

I'd boil it down to four key points.

First, prions are infectious proteins, PRP.

No DNA, no RNA.

Second, the mechanism is a shape shift.

Right.

Alpha helix, the good guy, goes to beta sheet, the bad guy.

And that beta sheet is resistant and causes a

Third, the result is spongiform encephalopathy.

Holes in the brain.

And this is key, no inflammation.

And finally, it is tough.

Incredibly tough.

Resistant to sterilization, resistant to the immune system, and unfortunately, 100 % fatal.

It's a sobering topic, but a fascinating one.

It reminds you that nature can be incredibly creative, even when it's destructive.

And I'll leave you with one final thought from the text.

That incubation period, four to 40 years.

It's strange to think that a simple change in the fold of a protein can lie dormant for decades,

just hiding in plain sight before triggering a cascade that destroys the mind.

Yeah.

It makes you wonder how many other, you know, molecular time bombs might be out there that we haven't discovered yet.

On that happy note, thanks for listening to The Deep Dive.

This has been a Last Minute Lecture Production.

We'll see you next time.

Stay cute.