So, we've talked about all
the first five bullet points.
I want to talk now about the
last bullet point, which is,
“Exotoxins and Endotoxins.”
What are those in terms of injury?
And what's being shown on the screen there, is,
“Group A streptococcus” with (scarlet
fever), the rash, the injury there,
is due to the release of an exotoxin.
I’m going to talk about another one here,
I’m talking about, cholera.
So, cholera is a non-invasive microorganism,
it is fecally, orally transmitted and kills,
because it causes a profound watery diarrhea
and basically, the poor affected
individual dies of dehydration.
So, how does cholera do this?
Well, it makes an exotoxin,
the exotoxin is actually important for the
cholera to get transmitted to its next host
obviously, if you've infected it, a host,
and they are defecating all over the place
because they have intractable diarrhea,
you're going to have a much better chance
of being transmitted to your next host,
so, it's part of what the bug wants to do,
in terms of its transmission,
but for the patient, let's
look at what happens here.
So, cholera toxin is composed
of an "A" toxic subunit
and a whole bunch of little "B" subunits,
that are important for binding,
the B subunits are the smaller
balls there at the bottom.
It binds, releases toxin A into the cell
and that toxin A, will end up, using,
nicotine adenine dinucleotide the NAD,
to ADP ribosylate G-protein, okay.
The exact names here are not all that important,
but this is going to be an important step,
in that it's now going to lead
to permanent activation of,
That intracellular enzyme, adenylate cyclase,
is going to be something that's going
to increase intracellular cyclic AMP
and when we increase intracellular cyclic AMP,
as shown here on the final slide,
we turn off sodium and chloride absorption
and turn on, impressive, chloride
and bicarbonate secretion,
and that's where that voluminous
watery diarrhea comes from
and that's the killer.
But this is not invasive,
but it caused lethal injury,
potentially lethal injury, by virtue
of the secretion of the exotoxin.
Let's do one other one, so endotoxin.
Endotoxin, will cause injury by
over activating the immune system.
Yeah, well that's what septic shock is all about.
So, endotoxin is a component of the
gram-negative bacteria cell wall,
it's normally present there.
It turns out that gram-positive
cocci, that's what the GPC is
and fungi have similar molecules, that
can induce an endotoxin-like result.
What is endotoxin?
It's a component of the
cell wall, yeah, I got that.
Okay, what is it really made of?
So, there is a, “carbohydrate O” component,
that's the green boxes up above,
that's unique to every particular bacteria,
every gram-negative bacteria,
but there is a common “lipid A” component,
that's attached to that
carbohydrate that polysaccharide,
that does all the devilish action
that we're going to be talking about.
And what it does, is that,
it activates macrophages,
that, “lipid A” component
of the lipopolysaccharide
or LPS activates macrophages.
How is this happening?
So, what's happening is that,
LPS on the bacterial cell wall
or as bacteria being destroyed,
the LPS, will bind to LPS binding protein,
this is a normal protein,
synthesized in the liver,
circulates around the body
and is responsible for
sopping up lipopolysaccharide
and saying, “Oh we have a potential infection,”
so, that's what that ball is at
the top, LBP is LPS binding protein
and the little wedge is lipopolysaccharide.
That complex will then bind
to CD14 on the cell surfaces,
of macrophage monocyte population,
as well as other cell types, such as, endothelium
and then we'll co-activate or
transactivate a toll-like receptor “TLR4,”
that's got a various adapter
proteins that's associated with it
and we'll get intracellular signaling.
So, by having the binding of the LPS-LBP
complex to CD14 and the toll-like receptor,
we now will make an inactive kinase, active,
we will phosphorylate a variety
of intracellular proteins.
Keep in mind that, locally this is a good thing,
we want to turn on the macrophages,
so they go after a particular bacteria
and do the right thing.
Okay, so we've gotten to the stage now,
where we're phosphorylating all those proteins,
we will, eventually through
a phosphorylation cascade,
get a transcription factor phosphorylated,
that goes into the nucleus of the cell,
macrophages and endothelial cells
and we'll get transcription of new,