Brain displays an intrinsic mechanism for fighting infection

Dec. 10, 2012 — White blood cells have long reigned as the heroes of the immune system. When an infection strikes, the cells, produced in bone marrow, race through the blood to fight off the pathogen. But new research is emerging that individual organs can also play a role in immune system defense, essentially being their own hero. In a study examining a rare and deadly brain infection, scientists at The Rockefeller University have found that the brain cells of healthy people likely produce their own immune system molecules, demonstrating an "intrinsic immunity" that is crucial for stopping an infection.

Shen-Ying Zhang, a clinical scholar in the St. Giles Laboratory of Human Genetics of Infectious Diseases, has been studying children with Herpes simplex encephalitis, a life-threatening brain infection from the herpes virus, HSV-1, that can cause significant brain damage. The scientists already knew from previous work that children with this encephalitis have a genetic defect that impairs the function of an immune system receptor -- toll-like receptor 3 (TLR3) -- in the brain. For this study they wanted to see how the defect in TLR3 was hampering the brain's ability to fight the herpes infection.

When TLR3 detects a pathogen it triggers an immune response causing the release of proteins called interferons to sound the alarm and "interfere" with the pathogen's replication. It's most commonly associated with white blood cells, found throughout the body, but here the researchers were examining the receptor's presence on neurons and other brain cells.

"One interesting thing about these patients is that they didn't have any of the other, more common herpes symptoms. They didn't have an infection on their skin or their mouths, just in their brains. We therefore hypothesized that the TLR3 response must be specifically responsible for keeping the herpes virus from infecting the brain and not necessary in other parts of the body," says Zhang.

The lab, headed by Jean-Laurent Casanova, collaborated with scientists at Harvard Medical School and Memorial Sloan-Kettering Cancer Institute to create induced pluripotent stem cells. Made from the patients' own tissue, the stem cells were developed into central nervous system cells that carried the patients' genetic defects. Zhang exposed the cells to HSV-1 and to synthetic double-stranded RNA, which mimics a byproduct of the virus that spurs the toll-like receptors into action. By measuring levels of interferon, Zhang showed that the patients' TLR3 response was indeed faulty; their cells weren't making these important immune system proteins, leaving them unable to fight off the infection.

Zhang also exposed the patients' blood cells to the virus and found that the TLR3 defect was not an issue there as it was in the brain -- interferons were released by other means.

Because the toll-like receptors on neurons proved to be vital in preventing the encephalitis infection, the researchers concluded that brain cells use it as an in-house mechanism to fight infection, rather than relying on white blood cells. When its function was impaired, patients couldn't get better.

"This is evidence of an intrinsic immunity, a newly-discovered function of the immune system," says Zhang. "It's likely that other organs also have their own specific tools for fighting infection."

The researchers are putting together a pilot study to test an interferon-based treatment in patients with the encephalitis, believing it will help speed recovery and increase the survival rate when used alongside antiviral drugs. They'll also explore whether the brain displays an intrinsic immunity to other types of viral infection.

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The above story is reprinted from materials provided by Rockefeller University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Fabien G. Lafaille, Itai M. Pessach, Shen-Ying Zhang, Michael J. Ciancanelli, Melina Herman, Avinash Abhyankar, Shui-Wang Ying, Sotirios Keros, Peter A. Goldstein, Gustavo Mostoslavsky, Jose Ordovas-Montanes, Emmanuelle Jouanguy, Sabine Plancoulaine, Edmund Tu, Yechiel Elkabetz, Saleh Al-Muhsen, Marc Tardieu, Thorsten M. Schlaeger, George Q. Daley, Laurent Abel, Jean-Laurent Casanova, Lorenz Studer, Luigi D. Notarangelo. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature, 2012; DOI: 10.1038/nature11583

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Novel RNA transport mechanism: Ribonucleoprotein granules exit the nucleus via a budding mechanism

ScienceDaily (May 10, 2012) — The movement of genetic materials, such as RNA and ribosomes, from the nucleus to the cytoplasm is a critical component in a cell's ability to make the proteins necessary for essential biological functions. Until now, it was believed the nuclear pore complex was the sole pathway between the cell nucleus and cytoplasm for these materials.

New evidence published in Cell by Vivian Budnik, PhD, professor of neurobiology, Melissa J. Moore, PhD, the Eleanor Eustis Farrington Chair in Cancer Research, Howard Hughes Medical Institute Investigator and professor of biochemistry & molecular pharmacology, and colleagues, reveals a novel budding mechanism, similar to the process used by some viruses, capable of exporting large ribonucleoprotein (RNP) particles from the nucleus to the cytoplasm.

"The findings in this paper fundamentally change our understanding of mRNA export from the nucleus," said Dr. Moore. "In addition to the canonical pathway of mRNA export going through the nuclear pore complex, we now know that large RNA transport granules can be assembled in the cell nucleus and exported via a budding mechanism previously thought to only be used by the herpes virus."

This study has helped to unravel how RNAs support the development of the post-synaptic apparatus, said Dr. Budnik. "It provides new evidence about communication between the nucleus and cytoplasm that has implications for diseases that affect the nuclear envelope such as muscular dystrophies and herpes-type infections such as shingles."

Found along the surface of the nuclear envelope, nuclear pores are small openings that allow certain molecules, such as messenger RNA, transfer RNA and ribosomes, to be transported across this physical barrier that separates a cell's nucleus and DNA from its cytoplasm. Once in the cytoplasm, these genetic materials are the factories and blueprints used by the cell to create proteins. In some cells, these RNAs are bound together in large clusters known as transport granules, which are carried to precise locations within a cell to synthesize specific proteins needed at that site.

"When we look at these transport granules to scale, we see that they're too large to pass through the nuclear pore complex," said Moore. "An open question has been, where are these transport granules first assembled? And if it's in the nucleus, how do they make their way to the cytoplasm?"

Working to understand how synapses develop and communicate with neighboring muscle cells, Budnik discovered a new method whereby these large granules, in the form of RNP particles, were transported across the nuclear envelope. Specifically, Budnik and colleagues were investigating how the Wnt/wingless (Wg) protein secreted by the motor neuron initiates a reaction involving the DFrizzled2 (DFz2) receptor on the nearby muscle cell. This interaction between Wg and DFz2 eventually leads a portion of the DFz2 into the muscle cell nucleus where it accumulates around large RNP granules containing messenger RNAs. Once they reach their final destination in the muscle cell cytoplasm, these RNAs are responsible for making the synaptic proteins critical to increasing the size of the junction between motor neuron and muscle cell.

It was while investigating this process that Budnik and colleagues witnessed these large granules exiting the muscle cell's nucleus in an unusual manner. "What was so surprising," said Sean D. Speese, PhD, former postdoctoral fellow in the Budnik lab and currently research assistant professor at Oregon Health and Sciences University, "was that the nuclear DFz2-large-RNPs utilized a novel mechanism for exiting the nucleus, which appeared independent of the nuclear pores and resembled the egress of herpes-type viruses from the nuclear envelope."

During infection, herpes virus particles are assembled in the nucleus. But they are much too large to exit through the nuclear pores. Instead, they bud through the double membranes of the nuclear envelope. To exit the nucleus, the protein shell surrounding the virus disrupts the lamina, a fibrous component located beneath the inner nuclear membrane which, among other properties, anchors the nuclear pore complexes to the nuclear membranes. This allows the virus to bud into the space between the inner and the outer nuclear membrane, becoming enveloped by the inner nuclear membrane. Fusion of this coat with the outer nuclear membrane then allows the virus to be released into the cytoplasm.

"Similarly, we found that DFz2C-RNPs used the same mechanism and viral machinery to reach the cytoplasm," said Dr. Speese. Once inside the muscle cell nucleus, the DFz2C RNPs recruit proteins, such as kinase C, to disrupt the lamins, which allows them to bud into the inner nuclear membrane. "In both cases, this process was dependent on an A-type lamina protein, which in humans is associated with a number of muscular dystrophies and early aging syndromes when mutated," said Speese.

Collectively, these discoveries have significant ramifications for our understanding of multiple biological questions including RNA transport, synapse development and the herpes virus, which causes chicken pox and shingles as well as Epstein-Barr virus, which causes mononucleosis.

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The above story is reprinted from materials provided by University of Massachusetts Medical School. The original article was written by Jim Fessenden.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Sean D. Speese, James Ashley, Vahbiz Jokhi, John Nunnari, Romina Barria, Yihang Li, Bulent Ataman, Alex Koon, Young-Tae Chang, Qian Li, Melissa J. Moore, Vivian Budnik. Nuclear Envelope Budding Enables Large Ribonucleoprotein Particle Export during Synaptic Wnt Signaling. Cell, 2012; 149 (4): 832 DOI: 10.1016/j.cell.2012.03.032

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here

Novel RNA transport mechanism: Ribonucleoprotein granules exit the nucleus via a budding mechanism

ScienceDaily (May 10, 2012) — The movement of genetic materials, such as RNA and ribosomes, from the nucleus to the cytoplasm is a critical component in a cell's ability to make the proteins necessary for essential biological functions. Until now, it was believed the nuclear pore complex was the sole pathway between the cell nucleus and cytoplasm for these materials.

New evidence published in Cell by Vivian Budnik, PhD, professor of neurobiology, Melissa J. Moore, PhD, the Eleanor Eustis Farrington Chair in Cancer Research, Howard Hughes Medical Institute Investigator and professor of biochemistry & molecular pharmacology, and colleagues, reveals a novel budding mechanism, similar to the process used by some viruses, capable of exporting large ribonucleoprotein (RNP) particles from the nucleus to the cytoplasm.

"The findings in this paper fundamentally change our understanding of mRNA export from the nucleus," said Dr. Moore. "In addition to the canonical pathway of mRNA export going through the nuclear pore complex, we now know that large RNA transport granules can be assembled in the cell nucleus and exported via a budding mechanism previously thought to only be used by the herpes virus."

This study has helped to unravel how RNAs support the development of the post-synaptic apparatus, said Dr. Budnik. "It provides new evidence about communication between the nucleus and cytoplasm that has implications for diseases that affect the nuclear envelope such as muscular dystrophies and herpes-type infections such as shingles."

Found along the surface of the nuclear envelope, nuclear pores are small openings that allow certain molecules, such as messenger RNA, transfer RNA and ribosomes, to be transported across this physical barrier that separates a cell's nucleus and DNA from its cytoplasm. Once in the cytoplasm, these genetic materials are the factories and blueprints used by the cell to create proteins. In some cells, these RNAs are bound together in large clusters known as transport granules, which are carried to precise locations within a cell to synthesize specific proteins needed at that site.

"When we look at these transport granules to scale, we see that they're too large to pass through the nuclear pore complex," said Moore. "An open question has been, where are these transport granules first assembled? And if it's in the nucleus, how do they make their way to the cytoplasm?"

Working to understand how synapses develop and communicate with neighboring muscle cells, Budnik discovered a new method whereby these large granules, in the form of RNP particles, were transported across the nuclear envelope. Specifically, Budnik and colleagues were investigating how the Wnt/wingless (Wg) protein secreted by the motor neuron initiates a reaction involving the DFrizzled2 (DFz2) receptor on the nearby muscle cell. This interaction between Wg and DFz2 eventually leads a portion of the DFz2 into the muscle cell nucleus where it accumulates around large RNP granules containing messenger RNAs. Once they reach their final destination in the muscle cell cytoplasm, these RNAs are responsible for making the synaptic proteins critical to increasing the size of the junction between motor neuron and muscle cell.

It was while investigating this process that Budnik and colleagues witnessed these large granules exiting the muscle cell's nucleus in an unusual manner. "What was so surprising," said Sean D. Speese, PhD, former postdoctoral fellow in the Budnik lab and currently research assistant professor at Oregon Health and Sciences University, "was that the nuclear DFz2-large-RNPs utilized a novel mechanism for exiting the nucleus, which appeared independent of the nuclear pores and resembled the egress of herpes-type viruses from the nuclear envelope."

During infection, herpes virus particles are assembled in the nucleus. But they are much too large to exit through the nuclear pores. Instead, they bud through the double membranes of the nuclear envelope. To exit the nucleus, the protein shell surrounding the virus disrupts the lamina, a fibrous component located beneath the inner nuclear membrane which, among other properties, anchors the nuclear pore complexes to the nuclear membranes. This allows the virus to bud into the space between the inner and the outer nuclear membrane, becoming enveloped by the inner nuclear membrane. Fusion of this coat with the outer nuclear membrane then allows the virus to be released into the cytoplasm.

"Similarly, we found that DFz2C-RNPs used the same mechanism and viral machinery to reach the cytoplasm," said Dr. Speese. Once inside the muscle cell nucleus, the DFz2C RNPs recruit proteins, such as kinase C, to disrupt the lamins, which allows them to bud into the inner nuclear membrane. "In both cases, this process was dependent on an A-type lamina protein, which in humans is associated with a number of muscular dystrophies and early aging syndromes when mutated," said Speese.

Collectively, these discoveries have significant ramifications for our understanding of multiple biological questions including RNA transport, synapse development and the herpes virus, which causes chicken pox and shingles as well as Epstein-Barr virus, which causes mononucleosis.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by University of Massachusetts Medical School. The original article was written by Jim Fessenden.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Sean D. Speese, James Ashley, Vahbiz Jokhi, John Nunnari, Romina Barria, Yihang Li, Bulent Ataman, Alex Koon, Young-Tae Chang, Qian Li, Melissa J. Moore, Vivian Budnik. Nuclear Envelope Budding Enables Large Ribonucleoprotein Particle Export during Synaptic Wnt Signaling. Cell, 2012; 149 (4): 832 DOI: 10.1016/j.cell.2012.03.032

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

View the original article here