Re: macrophage inactivation by Mtb - STAT1

[Guest guest]

I couldn't read this too well, having forgotten what TLR2 is for one thing. I got the depressing part in the conclusion though: These results establish that M. tuberculosis possesses multiple mechanisms of inhibiting responses to IFN-{gamma}.- KateOn Jun 6, 2006, at 3:08 PM, wrote:Wow, they are gettin way ahead of where they were when I studied this last year.These guyshttp://www.jimmunol.org/cgi/content/abstract/176/5/3019

[Guest guest]

I didnt read it myself, just kinda ransacked it.

TLRs are most chiefly, sensors of conserved microbial molecules. Tho

Polly Matzinger (a really interesting person and thinker) has some

stuff showing they may also respond to self molecules released by

tissue damage.

TLR ligation should be saying OMG KILL KILL KILL KILL KILL. But this

is like, oh, I'm sensing a bacterium via TLR-2, so I guess what I'll

do is NOT upregulate antibacterial effectors, and even if IFNg prods

me to do so, I'll just blow it off.

Where art thou, o proponants of Intelligent Design?

>

> I couldn't read this too well, having forgotten what TLR2 is for

one

> thing. I got the depressing part in the conclusion though: These

> results establish that M. tuberculosis possesses multiple

mechanisms

> of inhibiting responses to IFN-{gamma}.

>

> - Kate

>

[Guest guest]

After a receptor is filled, it's possible for there to be another stage

of processing, where the cell looks at exactly what filled the receptor,

and reacts only if it has certain properties. This sounds like what they

are trying to suggest:

" Macrophages lacking TLR2 are more resistant to inhibition by

either strain of M. tuberculosis, suggesting that nonlipoprotein

TLR2 agonists contribute to inhibition. "

which might be read as " Tuberculosis manages to keep TLR2 receptors

filled with nonlipoproteins, which don't trigger a response, blocking the

molecules that would trigger a response. "

On Tue, Jun 06, 2006 at 07:27:06PM -0000, wrote:

>I didnt read it myself, just kinda ransacked it.

>

>TLRs are most chiefly, sensors of conserved microbial molecules. Tho

>Polly Matzinger (a really interesting person and thinker) has some

>stuff showing they may also respond to self molecules released by

>tissue damage.

>

>TLR ligation should be saying OMG KILL KILL KILL KILL KILL. But this

>is like, oh, I'm sensing a bacterium via TLR-2, so I guess what I'll

>do is NOT upregulate antibacterial effectors, and even if IFNg prods

>me to do so, I'll just blow it off.

>

>Where art thou, o proponants of Intelligent Design?

>

>

>

>>

>> I couldn't read this too well, having forgotten what TLR2 is for

>one

>> thing. I got the depressing part in the conclusion though: These

>> results establish that M. tuberculosis possesses multiple

>mechanisms

>> of inhibiting responses to IFN-{gamma}.

>>

>> - Kate

[Guest guest]

Thanks for the translations, guys!- Katewhich might be read as "Tuberculosis manages to keep TLR2 receptorsfilled with nonlipoproteins, which don't trigger a response, blocking themolecules that would trigger a response.">>TLRs are most chiefly, sensors of conserved microbial molecules.

[Guest guest]

wrote: " >Where art thou, o proponants of Intelligent Design? "

Oh you can be so funny.

It's so complicated- we just don't have the answers...

It may be what's occupying a receptor, and subsequent signalling (or

not).. or it may be something else entirely.

Wanna see something very cool?

waht's this annimation of RNA interferrence.. and look at how

exquisitely sensitive our cells can be.

Barb

[Guest guest]

Norman Yarvin <norman.yarvin@...> wrote:

>

> After a receptor is filled, it's possible for there to be another

stage

> of processing, where the cell looks at exactly what filled the

receptor,

> and reacts only if it has certain properties. This sounds like

what they

> are trying to suggest:

>

> " Macrophages lacking TLR2 are more resistant to inhibition by

> either strain of M. tuberculosis, suggesting that

nonlipoprotein

> TLR2 agonists contribute to inhibition. "

>

> which might be read as " Tuberculosis manages to keep TLR2 receptors

> filled with nonlipoproteins, which don't trigger a response,

blocking the

> molecules that would trigger a response. "

I dont think your reading is what they are thinking - if it were,

they would have refered to those Mtb ligands as " antagonists " rather

than " agonists. "

Also, if Mtb were in fact deploying a TLR antagonist in order to

keep TLR2 from sensing Mtb's TLR2 agonists, then it would follow

that TLR2-knockout macrophages would behave the same as wild-type

macrophages. Whether blocked or absent, TLR2 would be doing the same

thing - ie, nothing. Instead, they say TLR2-knockouts are " more

resistant to inhibition, " suggesting that TLR2 probably has an

active role in the inhibition.

Its possible a molecule could be a " deranging agonist, " and by

binding to a receptor, put the receptor molecule into

some " unintended " conformation where it carries out some odd act

different from its intended act. I forget what a TLR even does to

pass on its signal once it gets ligandized and adopts an activated

conformation - but lets pretend it cyclizes AMP to cAMP, which in

turn triggers production of microbicidal peptides. A " poison " ligand

might get TLR into a conformation where it breaks down AMP instead

of cyclizing it. Thus, instead of pushing up [cAMP], it would pull

[cAMP] down. Now instead of a baseline concentration of microbicidal

peptides, we have none.

I dont know if any examples like this are known or not. There are

certainly some antimicrobial small molecules that cause proteins to

go on a deranged rampage (eg quinolones), but not by binding at a

receptor site, I believe.

[Guest guest]

Last week we had a speaker here at UVA discuss this late TLR-2-

mediated macrophage anergy, and a his forthcoming data on a (host)

transcription factor that seems to be involved.

While the involvement of a host transcription factor by no means

indicates that the phenomenon is host-directed, he postulated that it

probaby was, and could be intended for limiting immunopathy. I find

that hard to swallow, but it could be true. For instance, suppose

bacterium X were not destroyed efficiently by programmed cell death

or by any other effector mechanism - in that situation an X-infected

host might do well to have macrophages or granulomas bottle X up for

the duration of the host's life. If so, it would be very helpful for

these macrophages to *not* be screaming out 89 femto-tons TNF and IL-

12 on a permanent basis, because that makes the host sick.

If this actually happens, it could have a prominant role in aging,

which as a bioevolutionary puzzle is more unsolved than solved, or so

I'm told in class.

It also throws an interesting angle of light on a possibility we've

discussed in the past, which is that chronic immunergic disease might

result from a futile attack on a (postulated) non-aggressive

infection that is present in many or most humans and usually benign.

> On Tue, Jun 06, 2006 at 07:27:06PM -0000, wrote:

> >I didnt read it myself, just kinda ransacked it.

> >

> >TLRs are most chiefly, sensors of conserved microbial molecules.

Tho

> >Polly Matzinger (a really interesting person and thinker) has some

> >stuff showing they may also respond to self molecules released by

> >tissue damage.

> >

> >TLR ligation should be saying OMG KILL KILL KILL KILL KILL. But

this

> >is like, oh, I'm sensing a bacterium via TLR-2, so I guess what

I'll

> >do is NOT upregulate antibacterial effectors, and even if IFNg

prods

> >me to do so, I'll just blow it off.

> >

> >Where art thou, o proponants of Intelligent Design?

> >

> >

> >

> >>

> >> I couldn't read this too well, having forgotten what TLR2 is for

> >one

> >> thing. I got the depressing part in the conclusion though:

These

> >> results establish that M. tuberculosis possesses multiple

> >mechanisms

> >> of inhibiting responses to IFN-{gamma}.

> >>

> >> - Kate

>

[Guest guest]

So in some of us this transcription factor isn't working right and

our macrophages are screaming when they don't need to?

- Kate

On Nov 12, 2006, at 8:40 PM, wrote:

> While the involvement of a host transcription factor by no means

> indicates that the phenomenon is host-directed, he postulated that it

> probaby was, and could be intended for limiting immunopathy. I find

> that hard to swallow, but it could be true. For instance, suppose

> bacterium X were not destroyed efficiently by programmed cell death

> or by any other effector mechanism - in that situation an X-infected

> host might do well to have macrophages or granulomas bottle X up for

> the duration of the host's life. If so, it would be very helpful for

> these macrophages to *not* be screaming out 89 femto-tons TNF and IL-

> 12 on a permanent basis, because that makes the host sick.

[Guest guest]

> So in some of us this transcription factor isn't working right and

> our macrophages are screaming when they don't need to?

>

> - Kate

That's one possible molecular mechanism. But remember the whole idea

of us reacting violently to infections many people tolerate, is a

more or less made-up scenario.

It might explain the LYMERIX diseases particluarly sleekly, but I'm

not really convinced anything unusual is going on there in the first

place. Lots of vaccines cause rare severe side effects, some more

commonly than others I think. I think some papers concluded that

LYMERIX was normalish in this respect, which may or may not be true.

As I recall, the (apparantly-) broad Bb seroconversion seen in the

LYMERIX disease was extremely intriguing considering LYMERIX contains

only one protein (OspA). But then that guy LH Siegal brought out work

suggesting a lot of those bands could be aggregates and fragments of

OspA. While Siegal is the most rabidly patient-hating author I have

ever read or dreamed of, he may well be right about that matter.