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Borrelia burgdorferi reduces VDR expression
 Moderated by: Prof Trevor Marshall Page:    1  2  3  4  5  Next Page Last Page  
 

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Prof Trevor Marshall
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 Posted: Sun Jun 14th, 2009 04:04

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A new study has just been published, where a micro-array was used to see which human genes were affected by infection with Borrelia burgdorferi. This adds to the data we have on HIV and M.tuberculosis down-regulating VDR expression.

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000444

(here is the relevant data table with VDR in it)

Live Borrelia burgdorferi reduced VDR expression in monocytes by 50 times, and lysates ('dead' Borrelia) reduced it by 8 times (these ratios are not directly comparable with the HIV and TB studies Amy and I cite in our presentations).

So now we can understand the contribution which Borrelia burgdorferi adds to the metagenome...



ps: I would note that M.tb and Borrelia reduce the number of VDRs, rather than block the binding pocket with a ligand, such as capnine. It is believed that VDR is expressed by Estrogen-receptor-beta, but this is still tentative... The bugs know their target better than we do :X
 

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 Posted: Sun Jun 14th, 2009 06:18

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Dr Trevor Marshall wrote: ps: I would note that M.tb and Borrelia reduce the number of VDRs, rather than block the binding pocket with a ligand, such as capnine. It is believed that VDR is expressed by Estrogen-receptor-beta, but this is still tentative... The bugs know their target better than we do :X
 


Trevor,

I was wondering about this. This week, you already mentioned that M.Tb's effect wasn't through blocking the VDR itself.

Yet, Wang's table 1 does mention that the VDR transcribes itself, which would make it extremely vulnerable: knock the VDR out and it is gone. It would make sense that other receptors transcribe it, since we know how important it is. I guess that is called functional redundancy in the genome?

Forever learning, Frans  :)



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 Posted: Sun Jun 14th, 2009 07:38

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http://tinyurl.com/lko755

Not sure, but this article seems relevant.



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rick
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 Posted: Sun Jun 14th, 2009 16:56

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Does this now suggest that bacteria not only compromise our Vitamin D Receptors but also make some receptors permanently redundant?

What is the consequence of this if indeed we have a permanent net loss of our VDR quota and diminished antibacterial peptides?  

 

                                                             Rick



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Frans
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 Posted: Mon Jun 15th, 2009 03:01

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rick wrote: -1: Does this now suggest that bacteria not only compromise our Vitamin D Receptors but also make some receptors permanently redundant?

-2: What is the consequence of this if indeed we have a permanent net loss of our VDR quota and diminished antibacterial peptides?   

                                                             Rick


Rick:

-1: not redundant, but ineffective:  remember that rising levels of 25D and 1,25D start knocking out other receptors as well as the VDR and as we can tentatively conclude, the bacterial load shuts down other receptors as well as the VDR (in the case of Bb perhaps the Estrogen beta receptor, as shown above)

-2: you get a chronic disease ... However: the MP is designed to turn this around:  the actual DNA for the VDR, the other receptors and the antimicrobial peptides does not disappear, it is not being transcribed, so once things normalize again, transcription starts again, leading you to health

Hope this helps,

Frans



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 Posted: Mon Jun 15th, 2009 07:09

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Dr Trevor Marshall wrote:
I would note that M.tb and Borrelia reduce the number of VDRs, rather than block the binding pocket with a ligand, such as capnine.


This study says that M.tb downregulates expression:
http://www.cmj.org/Periodical/paperlist.asp?id=LW9156&linkintype=pubmed

Is there another study you're thinking of or did I misread this? I wouldn't ask were it not for the KB.

Paul



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 Posted: Mon Jun 15th, 2009 08:04

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@Paul: Are you looking for the reference Dr. Marshall provided in the first post of the thread maybe?



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paulalbert
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 Posted: Mon Jun 15th, 2009 08:22

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Maybe the problem is that the implications of the paper Trevor references is too subtle for me to get.

The impetus for the question came from the fact that there is other research that shows Bb downregulates expression of the VDR. In the PLoS Pathogens paper Trevor refers to there is (at least according to Trevor) a different mode of action.

I was just wondering if:
1. Bb really cleaves the VDR in particular. There is no indication in the paper I can see beyond generic talk of cleaving and references to caspase-1, which belongs to a family known for cleaving receptors.
2. If yes, I was wondering if this action compliments/contradicts the research referred to here in which Bb downregulates VDR expression (downregulating and cleaving are different!):
http://mpkb.mp-dev.com/doku.php/home:pathogenesis:vitamind:metabolism#bacteria_disable_the_vdr

I'm trying to make a habit of not including anything in the KB that I don't get. Therefore, I would rather not include this paper until I see how it fits into its proper context.

Paul



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Prof Trevor Marshall
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 Posted: Mon Jun 15th, 2009 10:58

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Paul,
If you look at the differential expression of the VDR on the second to last entry in Table S2 of the paper I cite you can see that expression of the VDR is downregulated by 50 times (0.02) and 8 times (.12) by the Borrelia infection :):)
 
Expression by the VDR may also be affected (eg by capnine etc) but that isn't clear by looking at the data they collected.
 

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 Posted: Sat Jun 27th, 2009 04:50

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Treor,

I just found this paper, the latest on VDR. VDR also seems to be downregulated by EBV.

Expression profile of nuclear receptors upon Epstein - Barr virus induced B cell transformation.  PMID:  19550398

I cannot access the full-text to see how manyfold it is downregulated, or by what mechanism, perhaps someone can look at it?

Frans

Last edited on Sat Jun 27th, 2009 04:52 by Frans



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 Posted: Sat Jun 27th, 2009 07:32

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Great find, Frans!

Here's the full text:
http://www.exp-oncology.com.ua/download/755.pdf

Paul

Last edited on Sat Jun 27th, 2009 07:33 by paulalbert



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Frans
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 Posted: Sat Jun 27th, 2009 08:06

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Thanks Paul,

Patrick was even faster in sending a link to the full-text  :D

I am trying to figure out how manyfold the VDR was downregulated, but concentration is lacking.

There are, however, some things that occurred to me.

1: it seems as if bacteria and viruses that have been implicated in a lot of autoimmune (chronic TH1) diseases, like EBV and borrelia ALL act through downregulating the VDR;  of course, this makes sense, considering the role the VDR plays in innate immunity ...  This might in fact be WHY they are always implicated ... and now we understand why

2: this might also give an indication of why infection by these critters pushes people over the brink, right into th1 disease

3: this particular paper might also give an insight as to why EBV infection (I am thinking of Pfeiffer's disease as we call it (you guys call it the Kissing disease?) is so hard to conquer;  innate immunity is severely compromised, so healing takes a long time

Something else just occurred to me:  I have seen in pubmed that MicroRNA's play a role in VDR transcription. Wiki tells me EBV encodes several microRNA's, for what it is worth ..  Perhaps those microRNA's are involved in the machanism by which EBV downregulates the VDR. Of course, this a reaching a little ...  ;)

Frans

Edit:  EBV does NOT cause cold sores. EBV is a Human herpes virus (number 4), but not all Herpes viruses are EBV's ... If I am not mistaken, cold sores are caused by Herpes simplex. Not EBV.  concentration on MP remains an issue...

Last edited on Sat Jun 27th, 2009 13:54 by Frans



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Prof Trevor Marshall
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 Posted: Sat Jun 27th, 2009 12:47

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Frans,
The 3D-graph is plotted as Log(concentration ratio) and I estimate about 5 times for VDR.You might like to cross-check my numbers.
 
As for micro-RNAs, note that the Estrogen-beta receptor is not down-regulated. Since VDR is believed to be expressed primarily by Er-beta, that implies (for me) that the mechanism of downregulation is a ligand targeting Er-beta. Micro-RNAs are an unlikely ligand, although I admit I haven't tried to dock them...
 

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 Posted: Sat Jun 27th, 2009 13:49

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Trevor,

Somehow transcription of VDR and transcription by VDR keeps confusing/eluding me. PMID: 19437538  shows miRNA influencing transcription by VDR, not of VDR. My mistake.

But if I am not mistaken, ER beta is also downregulated by EBV ? It is mentioned in table 1 under receptors being downregulated.

In graph 2a VDR and ER beta show a similar slope, going up a little, until about 48 hours, but ending lower. ER-beta is the green one :)

5 times downregulation is a serious impact btw.

As for checking your numbers: I don't think I have the capability or knowledge at this time, to say the least :?   Ah well, MP is not endless  :D  Life after it might very well be, hehe :cool:

Frans



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 Posted: Sat Jun 27th, 2009 14:15

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Reading this thread makes it clear to me that VDR blockage (from bacterial ligands and from ingested Vitamin D) is not the only way in which the immune system of a patient with TH1 disease is compromised.  The pathogens mentioned in this thread downregulate the expression of the VDR itself (by targeting receptors responsible for VDR expression) and there are probably other pathogens that have evolved even more creative ways for disrupting the immune system.

The main part of the MP, activating the VDR with Benicar and avoidance of ingested Vitamin D, will counteract blockage of the VDR with bacterial ligands, but my understanding is that it would not have a direct affect in combating downregulation of the VDR or other mechanisms the bacteria might employ.  This brings a number of questions into my mind...

Is the expectation that though there are other ways in which the immune system is weakened, that VDR blockage is the main one, and that once this blockage is removed, even if the number of VDRs is reduced thru downregulated expression, that this will restore immune function enough that it can start to go to work on all pathogens, regardless of the mechanisms they are employing?

Is it fair to say that the degree to which all the various immune system weakening mechanisms are employed by a particular patient's bacterial soup (how much is bacteria that block the VDR with ligands, how much is bacteria that downregulate expression of the VDR, etc.) would be a key factor in how they respond to the MP?

Might a patient with a bacterial soup that has a high degree of down-regulation of the VDR require more help from antibiotics than a patient who has a bacterial soup that is mainly just blocking the VDR with ligands?

Thanks!

- Russ

p.s. I only partially take for granted the fact that we have a scientist "working for us", who is completely on top of all the new studies that come out and can explain them to us.  :)



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paulalbert
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 Posted: Sat Jun 27th, 2009 14:47

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Russ wrote:
Might a patient with a bacterial soup that has a high degree of down-regulation of the VDR require more help from antibiotics than a patient who has a bacterial soup that is mainly just blocking the VDR with ligands?


Unless I misunderstand your question, Russ, I think they're the same thing. Excepting the effects of viruses such as EBV, how else does a VDR get downregulated??? Certainly not by itself.

Paul



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Russ
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 Posted: Sat Jun 27th, 2009 15:08

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Hi Paul.  I probably didn't word that well.  These are the two mechanisms I was trying to differentiate between:

1. Bacteria that produce a ligand (e.g. capnine) that blocks the VDR.  Benicar is effective at displacing this ligand from the VDR and re-activating it.

2. Bacteria that produce a ligand that blocks, for example, the Estrogen-beta receptor which Dr. Marshall has said is likely responsible for VDR expression.  The result here would not be a blocked VDR but a VDR that is not expressed.  I don't think Benicar would be directly effective in combating this down-regulation...I would think you'd need an agonist of the Estrogen-beta receptor to displace the ligand that is blocking that.

I may be missing something, but this is how I was understanding the difference between blocking a receptor and down-regulating it's expression.

- Russ



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 Posted: Sat Jun 27th, 2009 15:21

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Russ,
The two things will both be happening at once. Some species doing one thing, some species the other. Benicar will always be useful in trying to start the process of disease reversal.

The extreme case, of course, is the chronic phase of HIV/AIDS. Murdoch University has one of the world's leading research teams in HIV/AIDS, and I spent some time working through these issues in my mind while I was visiting Murdoch last week :):)
 
http://www.murdoch.edu.au/About-Murdoch_old/Murdoch-discoverers/Professor-Simon-Mallal/
 
http://www.genesiis.murdoch.edu.au/simon_mallal.html
 

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 Posted: Sun Jun 28th, 2009 13:45

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Hi Frans,
I think you are not off-base by suspecting that RNA interference and related RNA mechanisms are likely involved in the processes by which the human microbiota exert their profound influence on its host.  Micro-RNAs are single-stranded RNAs that primarily downregulate protein production by inhibition of protein translation from messenger RNAs (mRNAs).  Thus, production of microRNAs that target either or both of the the estrogen receptor or the VDR could reduce VDR production and activity.  Researchers are beginning to document the production of micro and siRNA (small interfering) double-stranded RNA molecules in pathogenic bacteria, their operation in host cells and their association with disease (cancer, in particular).

The mechanisms by which the small RNA classes can affect gene expression are amazing and still being discovered; they can disrupt both protein translation and transcription, and even affect protein function and longevity post-transcriptionally.  They are involved in alternate forms of host protein splicing - different 'splice variants' of the same protein can function very differently in the host.  I am not aware of small RNAs that act as ligands for host receptors, but anything is possible. 

The researchers at West China hospital have the molecular expertise and equipment to help sort things out at the intracellular level in the human host.  I am also hopeful that Amy will be pursuing these matters in her graduate work.  There are exciting things to come in the next few years,
Ruth




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 Posted: Tue Nov 17th, 2009 10:59

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I am having a follow-up appt with my Endo who is also a bone specialist (Ha!) on Mon Dec 7th..(I am 44 rys old and have osteopenia, so she is monitoring me.)

She is going to "freak" :shock: when she sees how low my 25-D levels are now this year..So I would like to take just 1-2 mins of her time to explain in point forms, why I am avoiding Vit D and why my 25-D levels need to stay low at this time...etc.

Can someone please help me with this...This is my understanding of it all, but I may have my facts mixed up.

1. The VDR controls the innate immune system.

2. People who have Th1 diseases have CWD bacteria (in their phagocytes) which block some enzyme?  This is turn causes a rise in the levels of 1-25D in the body.

3. Elevated levels of 1-25 D (above what level?), cause the innate immune system to shut down, so it can no longer fight the intracellular bacteria.

4. When the 1-25 D goes up the 25-D tends to go down.

5. We need to keep the 25-D below 12 ng/ml because taking in any Vit D will cause a conversion into 25-D which in turn will cause 1-25 to rise, which if goes too high (above what number?) will cause the innate immune system to shut down again.

6.We take Benicar b/c it unblocks the VDR from 1-25D? and it allows the innate immune system to wake up and see and attack the CWD once again.

How did I do..yes?  no?   :D

I will also be leaving her some research papers etc...for her to read...Ha..like that's going to happen? :P

Thanks!!



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Dec'16-25D=28 ng/ml|1,25D =60.42 pg/ml
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