Topic: TODAY> Scientists find protein that helps bacteria misdirect immune system
steve1906
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Scientists find protein that helps bacteria misdirect immune system
A team led by scientists at The Scripps Research Institute (TSRI) has discovered an unusual bacterial protein that attaches to virtually any antibody and prevents it from binding to its target.
Protein M, as it is called, probably helps some bacteria evade the immune response and establish long-term infections. If follow-up studies confirm Protein M's ability to defeat the antibody response, it is likely to become a target of new antibacterial therapies. The protein's unique ability to bind generally to antibodies also should make it a valuable tool for research and drug development.
"What Protein M does to antibodies represents a very clever trick of evolution," said Richard A. Lerner, MD, Lita Annenberg Hazen Professor of Immunochemistry and Institute Professor at TSRI who led the research. The new findings, which were achieved through collaboration among several laboratories at TSRI and elsewhere, are described in the journal Science.
The unexpected discovery originated from an effort to understand the origin of multiple myeloma, a B-cell carcinoma. Clonal B-cell proliferation, as well as lymphomas and myelomas, can result from chronic infections by organisms such as Escherichia coli, Helicobacter pylori and hepatitis C virus.
To better understand this process, the team investigated mycoplasma, a parasite that infects people chronically and is largely confined to the surface of cells.
In a search for factors associated with long-term mycoplasma infection, Rajesh Grover, PhD, a senior staff scientist in the Lerner laboratory, tested samples of antibodies from multiple myeloma patients' blood against a variety of mycoplasma species. One of the proteins recognized by the antibodies was from Mycoplasma genitalium, which causes sexually transmitted infections in humans.
To the scientists' surprise, every antibody sample tested showed reactivity to this protein. But further tests made clear that these antibody reactions were not in response to mass infection with M. genitalium. Instead, the scientists found, the mysterious M. genitalium protein appeared to have evolved simply to bind to any antibody it encounters.
That presents a potentially major problem for the immune system. The antibody response is meant to combat invading pathogens with precisely targeted attacks, each selected from an enormous repertoire of hundreds of millions of distinct antibodies. In effect, the system is designed not to bind universally to any one target. If it did, then such a target could act as a universal decoy, potentially nullifying the entire antibody response.
The current research suggested that M. genitalium has evolved such a decoy. "It binds to every antibody generically—capable of hijacking the entire diversity of antibody repertoire—but at the same time it blocks the specific interaction between that antibody and its intended biomolecular target," said Grover. The team decided to call it "Protein M."
To better how understand Protein M works, Xueyong Zhu, PhD, a staff scientist in the laboratory of Ian Wilson, DPhil, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI, and colleagues took a structural biology approach.
Using X-ray crystallography and other techniques, including electron microscopy in the TSRI lab of Assistant Professor Andrew Ward, PhD, the team determined the protein's 3D atomic structure while the protein was bound to various human antibodies.
Compared to thousands of known structures in the Protein Data Bank, the worldwide structure database, Protein M appeared to be unique. The data also revealed that Protein M binds to a small, unchanging—"conserved"—region at the outer tip of every antibody's antigen-binding arm. "It likely extends the other end of itself, like a tail, over the antibody's main antigen-binding region," Zhu said.
The team is now studying Protein M's function during M. genitalium infections. It seems likely that the oddball protein evolved to help M. genitalium cope with the immune response despite having one of the smallest bacterial genomes in nature.
"It appears to represent an elegant evolutionary solution to the special problem that mycoplasma have in evading the adaptive immune system," said Grover. "The smallest parasitic bacteria on planet earth seems to have evolved the most sophisticated invading molecular machine."
If Protein M is confirmed as a universal decoy for antibodies, it will become a target for new drugs, which could make it easier to treat chronic, sometimes silent infections by M. genitalium and by any other microbes that have evolved a similar antibody-thwarting defense. Chronic infections can lead to a host of other problems, including inflammatory diseases and cancers.
In principle, Protein M also could be engineered to target specific groups of B cells—immune cells that produce antibodies and express them on their surfaces. Thus, Protein M could deliver cell-killing toxins to cancerous B cells but not healthy ones, for example to treat certain lymphomas.
In the era of antibody-based drugs, the most immediate use of Protein M is likely to be as a tool for grabbing antibodies in test tubes and cell cultures, useful for the preparation of highly pure antibody for research and drug manufacturing.
Other generic antibody-binding proteins have been put to use in this way, but so far it appears that none does the job quite as well as Protein M. "It may be the most useful antibody purification device ever found," said Lerner, who is already in talks with industry to commercialize the protein.
Rajesh K. Grover, Xueyong Zhu, Travis Nieusma et al.: A Structurally Distinct Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union. Science, Vol. 343, pp. 646-660, doi:10.1126/science.1246135
-------------------- Everything I say is just my opinion! Posts: 3529 | From Massachusetts Boston Area | Registered: Jul 2008
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Keebler
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- A, A, Amazing Article. Merci Beaucoup. I very much like that they looked at mycoplasma and say it can very much be chronic. We've all known that for years but most doctors do not.
I wonder what Garth Nicholson, PhD would say about this. He's a fabulous researcher who has worked his career around mycoplasma.
Wondering about the institution of the researchers:
The Scripps Research Institute (TSRI) is a nonprofit research institution whose philosophy emphasizes the creation of basic knowledge in the biosciences
for its application in medicine, the pursuit of fundamental scientific advances through interdisciplinary programs and collaborations, and the education and training of researchers preparing to meet the scientific challenges of the future.
Campuses
The Scripps Research Institute has two campuses: its headquarters in La Jolla, CA, and a new facility in Jupiter, FL.
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While the research above seems to focus on one strain (Mycoplasma genitalium, which causes sexually transmitted infections in humans) . . .
Related to topic of mycoplasma in general (VARIOUS STRAINS, though) - and to compare "notes", although not necessarily connected with the article above (that I could tell by a quick glance):
Prof. Garth Nicholson's research in Mycoplasma is to be commended. He does not treat. Still, he is THE top expert researcher in this field (although that does not mean others don't have some good insight, too).
He has presented several times at ILADS annual conferences and is well known and respected in the ILADS community.
Mycoplasma website (Garth Nicholson, PhD, researcher) -
Posts: 48021 | From Tree House | Registered: Jul 2007
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Keebler
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- On the link posted by Steve, look to the right hand menu for other interesting research. Just one area, perhaps that would also be helpful re: babesia. Glad to know there are people out there working on all these things.
-------------------- Everything I say is just my opinion! Posts: 3529 | From Massachusetts Boston Area | Registered: Jul 2008
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Keebler
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- So far, I've looked mostly at the pretty pictures (it will take me a very long time to read it all) . . . I know they are colored by dyes, etc. still, hard to think that something so intricate can be so destructive.
And, to think that so many doctors really believe that if "science" and "medicine" have not found something to date (or by the time they left medical school) that problems have to be all in a patient's imagination.
Never has a doctor who kicked me out the door ever said: "you know, there is still much to be discovered about illness." -
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Keebler
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- Another group to look to for medical research in general is the Howard Hughes "group" (Institute?). My impression is that they are more independently minded. -
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poppy
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quote:The unexpected discovery originated from an effort to understand the origin of multiple myeloma, a B-cell carcinoma. Clonal B-cell proliferation, as well as lymphomas and myelomas, can result from chronic infections by organisms such as Escherichia coli, Helicobacter pylori and hepatitis C virus.
That was a shocker. I have heard of H. pylori and stomach cancer, but lymphoma and myeloma from chronic infections!!!!!
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Razzle
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Most "in the know" doctors believe infection of some kind or another is behind all cancer.
Vets know leukemia in cats is caused by a virus...
Many believe certain forms of cancer are caused by viral or fungal infections...
Celiac Disease, thought by some experts to be triggered or activated by bacterial food poisoning, dramatically increases the risk of lymphoma in the gut.
-------------------- -Razzle Lyme IgM IGeneX Pos. 18+++, 23-25+, 30++, 31+, 34++, 39 IND, 83-93 IND; IgG IGeneX Neg. 30+, 39 IND; Mayo/CDC Pos. IgM 23+, 39+; IgG Mayo/CDC Neg. band 41+; Bart. (clinical dx; Fry Labs neg. for all coinfections), sx >30 yrs. Posts: 4166 | From WA | Registered: Feb 2011
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My supportive 2 cents to Razzle's statement above.... I believe fungal infections can certainly be linked with some cancers. I have (had) a small bcc lesion on my shoulder. It has almost completely resolved in the past 2 weeks. Only thing going on out of the ordinary is that I have been taking oral anti-fungals for about 1 month. The anti-fungals were prescribed for a high candida antibody test after my last round of abx.
This was quite unexpected. The lesion was there for about 2 years... and poof, now practically gone. Things that make you go hmmmmm.
I am not suggesting anti-fungals can help others with bcc's, but it certainly helped me. I welcome all good fortune:) I had a bcc surgically removed about 7 years ago. I started getting things checked out after that point which is the only reason I knew about the one on my shoulder.
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WPinVA
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Wow, so this explains how our immune systems can be going non-stop and yet not be effective at the same time.
So, given that any new treatments from this would be years off, any ideas of how this new knowledge could be harnessed given existing Lyme treatments?
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poppy
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Not sure it would be true that all cancer is caused by infections. Think of smoking, various chemicals that have been implicated, not to mention radiation, etc. So, probably more infectious agents than we know are behind cancers, but not all are from infections.
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steve1906
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. . . Charting the Path from Infection to Cancer
-------------------- Everything I say is just my opinion! Posts: 3529 | From Massachusetts Boston Area | Registered: Jul 2008
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Marnie
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Steve...wow, what a link...with pictures too!
Okay...fairly recently we found out Bb picks up a protein in the tick's saliva called p8.
That protein looks to be a retroviral protein called HTLV-1. It was the first retroviral protein researchers found that can trigger cancer.
(HIV was first called HTLV-III.)
Retroviral proteins are present in MILLIONS of people (like HERV-W - the "W" represents tryptophan...took me a long time to find that). THAT is the retroviral protein that triggers "autoimmune" MS.
It appears these proteins can continually activate NFkB.
Not a good situation.
But what triggers them to become "active" (if they are in most of us) is still unknown (at least to me).
Here is the abstract and link about Bb and p8:
The Lyme disease agent Borrelia burgdorferi is primarily transmitted to vertebrates by Ixodes ticks.
The classical and alternative complement pathways are important in Borrelia eradication by the vertebrate host.
We recently identified a tick salivary protein, designated P8, which reduced complement-mediated killing of Borrelia.
We now discover that P8 interferes with the human lectin complement cascade, resulting in impaired neutrophil phagocytosis and chemotaxis and diminished Borrelia lysis.
Therefore, P8 was renamed the tick salivary lectin pathway inhibitor (TSLPI).
TSLPI-silenced ticks, or ticks exposed to TSLPI-immune mice, were hampered in Borrelia transmission.
Moreover, Borrelia acquisition and ***persistence in tick midguts*** was impaired in ticks feeding on ***TSLPI-immunized***, B. burgdorferi-infected mice.
Together, our findings suggest an essential role for the lectin complement cascade in Borrelia eradication and demonstrate how a vector-borne pathogen co-opts a vector protein to facilitate early mammalian infection and vector colonization.
Okay...less Bb in ticks' midguts too? What factor in the blood of the WFL maybe capable of inhibiting p8? Sorry...had to go there.
A vaccine (yes...I know the dangers!) to p8 (a retroviral protein) maybe someday helpful.
P.S. ONGOING inflammation...release of inflammatory cytokines is NOT HEALTHY. The Romanian docs who cured EARLY onset lyme via restoring Mg levels (anti-inflammatory AND anti-histamine) AND gave IV abx. got it right.
Tame down the immune response and target the pathogen.
BTW...10-15% of Bb(s) can actually invade and live IN HeLa cells....I linked previously. That, to me, is mind blowing.
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poppy
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How about some good news? This is depressing me.
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steve1906
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. . Poppy, I'm sorry to have depressed you, so I'm hoping this little joke puts a smile on your face.
[b]Who Says Men Don't Remember
A couple were Christmas shopping. The shopping center was packed , and as the wife walked through one of the malls she was surprised when she looked around to find that her husband was nowhere to be seen. She was quite upset because they had a lot to do and she became so worried that she called him on her mobile phone to ask him where he was.
In a quiet voice he said, "Do you remember the jewelers we went into about five years ago where you fell in love with that diamond necklace that we couldn't afford, and I told you that I would get it for you one day?"
The wife choked up and started to cry and said, "Yes, I do remember that shop."
He replied, "Well, I'm in the bar next door."
Steve
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Marnie
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A husband actually went Christmas shopping in a center with his wife?
;-)
Mine heads for Best Buy or the Apple store...
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nefferdun
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I get the joke (very funny) but the rest of it is pretty much over my head - just more bad news about how this stuff tricks our immune system.
-------------------- old joke: idiopathic means the patient is pathological and the the doctor is an idiot Posts: 4676 | From western Montana | Registered: Apr 2009
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