The Ultimate Decoy: A Protein that Helps Bacteria Misdirect Immune System

03 February 2014 The Scripps Research Institute

A team led by scientists at The Scripps Research Institute has discovered an unusual bacterial protein that attaches to virtually any antibody, possibly helping bacteria establish long-term infections. Compared to thousands of known structures, this protein appears to be unique. 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.

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“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 February 7, 2014 issue of the journal Science.

Unexpected Discovery

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 (E. coli), Helicobacter pylori (H. 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.

‘Protein M’

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.

“The smallest parasitic bacteria on planet earth seems to have evolved the most sophisticated invading molecular machine.”

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.”

Unusual—and Unusually Useful

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.

“It may be the most useful antibody purification device ever found,”

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.

The Team

In addition to Lerner, Wilson, Grover and Zhu, authors of the study, “A Structurally Unique Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union,” were TSRI’s Travis Nieusma, Teresa Jones, Isabel Boreo, Amanda S. MacLeod, Adam Mark, Sherry Niessen, Helen J. Kim, Leopold Kong, Vaughn V. Smider, Daniel R. Salomon and Andrew B. Ward; Nacyra Assad-Garcia, Keehwan Kwon and John I. Glass of the J Craig Venter Research Institute in Rockville, MD; Marta Chesi of the Mayo Clinic Arizona; Diane F. Jelinek and Robert A. Kyle of the Mayo Clinic College of Medicine in Rochester, MN; and Richard B. Pyles of the University of Texas Medical Branch, Galveston, TX.

The study was funded in part by the National Institutes of Health (RO1 AI042266, R21 AI098057, R01 AG020686, K08 AR063729, RR017573, U19 AI06360).

Source: The Scripps Institute

Researchers Discover How to Shutdown Cancer’s Powerful Master Protein


Weill Cornell Research Offers Patients Hope for New Treatments for an Aggressive and Common Lymphoma

NEW YORK (March 3, 2013— The powerful master regulatory transcription factor called Bcl6 is key to the survival of a majority of aggressive lymphomas, which arise from the B-cells of the immune system. The protein has long been considered too complex to target with a drug since it is also crucial to the healthy functioning of many immune cells in the body, not just B cells gone bad.

Getting A Fix On Immune CellsBut now, in the journal Nature Immunology, researchers at Weill Cornell Medical College report that it is possible to shut down Bcl6 in the cancer, known as diffuse large B-cell lymphoma (DLBCL), while not affecting its vital function in T cells and macrophages that are needed to support a healthy immune system.

“The finding comes as a very welcome surprise,” says the study’s lead investigator, Dr. Ari Melnick, Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell. 

“This means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized,” says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

If Bcl6 is completely inhibited, patients might suffer from systemic inflammation and atherosclerosis. Weill Cornell researchers conducted this new study to help clarify possible risks, as well as to understand how Bcl6 controls the various aspects of the immune system.

DLBCL is the most common subtype of non-Hodgkin lymphoma — the seventh most frequently diagnosed cancer — and many of these patients are resistant to currently available treatments.

“Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies,” Dr. Melnick says. “Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs.”

In fact, the findings in this study were inspired from preclinical testing of two Bcl6-targeting agents that Dr. Melnick and his Weill Cornell colleagues have developed to treat DLBCLs. These experimental drugs are RI-BPI, a peptide mimic, and the small molecule agent 79-6. 

Dr. Melnick says the discovery that a master regulatory transcription factor can be targeted offers implications beyond just treating DLBCL. Recent studies from Dr. Melnick and others have revealed that Bcl6 plays a key role in the most aggressive forms of acute leukemia, as well as certain solid tumors. 

Transcription factors are responsible for either inhibiting or promoting the expression of genes, and master regulatory transcription factors are the equivalent of the CPU of a computer – their actions regulate thousands of genes in different kinds of cells. For example, Bcl6 can control the type of immune cell that develops in the bone marrow — playing many roles in the development of B cells, T cells, macrophages and other cells — including a primary and essential role in enabling B-cells to generate specific antibodies against pathogens. 

“When cells lose control of Bcl6, lymphomas develop in the immune system. Lymphomas are ‘addicted’ to Bcl6, and therefore Bcl6 inhibitors powerfully and quickly destroy lymphoma cells,” Dr. Melnick says.

The big surprise in the current study is that rather than functioning as a single molecular machine, Bcl6 instead seems to function more like a Swiss Army knife, using different tools to control different cell types. This multi-function paradigm could represent a general model for the functioning of other master regulatory transcription factors.

“In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type,” Dr. Melnick says. “For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer. You don’t need to eliminate the whole knife,” he says. “In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need.”

Prior to these study results, it was not known that a master regulator could separate its functions so precisely. 

“Now we know we can take out a specific tool — to shut down a specific part of the protein — that causes the disease we want to treat.”

Researchers hope this will be a major benefit to the treatment of DLBCL and perhaps other disorders that are influenced by Bcl6 and other master regulatory transcription factors.

Study co-authors include Dr. Chuanxin Huang and Dr. Katerina Chatzi from the Division of Hematology and Oncology at Weil Cornell Medical College.

The research was funded by grants from the National Cancer Institute, The Burroughs Wellcome Foundation and the Chemotherapy Foundation. The research was initially supported by a March of Dimes Scholar Award and facilitated by the Sackler Center for Biomedical and Physical Sciences at Weill Cornell. 




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