Science Signaling Podcast: 07 October 2008

Science Signaling  07 Oct 2008:
Vol. 1, Issue 40, pp. pc9
DOI: 10.1126/scisignal.140pc9


This conversation is about research highlighted in the Editors' Choice summary titled, “Promoting an Inactivating Partnership.” The highlighted article is G. Hajishengallis, M. Wang, S. Liang, M. Triantafilou, K. Triantafilou, “Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function,” Proc. Natl. Acad. Sci. U.S.A. 105, 13532–13537 (2008).

(Length: 7 min; file size: 3.26 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_081007.mp3)

Technical Details

Length: 7 min

File size: 3.26 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Download Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_081007.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Microbiology, Cell Biology, Immunology

Keywords: Science Signaling, signal transduction, microbiology, periodontitis, gingivitis, virulence, fimbriae, CXCR4, TLR, bacteria


John FoleyWelcome to the Science Signaling Podcast. I'm John Foley. In this podcast, we'll talk about a study that describes a mechanism for how the bacteria that cause periodontitis can inhibit the immune response. The original research for the basis of this discussion was published in the September 9th issue of the Proceedings of the National Academy of Sciences (1). A summary of the research article we’ll be discussing today appeared in the Editors’ Choice section of Science Signaling on September 16th (2). Today, Science Signaling editor Nancy Gough is here with me to talk about this research.

John FoleyHello, Nancy.

Nancy GoughHi, John.

John FoleySo, this study is about the bacteria that cause periodontitis. That's the inflammation of the tissue around the teeth that can cause tooth loss, correct?

Nancy GoughYes, it is. It's a painful infection that in adults is typically caused by bacteria called Porphyromonas gingivalis. As many as 49 million Americans may have some form of periodontal disease. P. gingivalis are gram-negative bacteria that take over the oral cavity from the less harmful gram-positive bacteria that are typically found in the mouth.

John FoleyHow do the bacteria avoid the body's immune system?

Nancy GoughWell, what Hajishengallis and colleagues found was that the fimbriae or hairlike extensions of P. gingivalis can disrupt the signaling of TLR2, a receptor that is used by the body to sense and respond to bacterial infections.

John FoleyHow do the fimbriae do that, exactly?

Nancy GoughWell, the fimbriae consist of proteins that are specific to each type of bacteria. And, for P. gingivalis, the fimbriae allow the bacteria to invade the gums and are virulence factors required for the bacteria to produce disease.

In particular, Hajishengallis and colleagues found that one way the fimbriae help the bacteria is by stimulating a particular chemokine receptor called CXCR4.

John FoleyWhat does CXCR4 do?

Nancy GoughWell, CXCR4 is a G protein-coupled receptor involved in allowing various types of cells, including cells of the immune system, to respond to signals to migrate.

John FoleySo, how does stimulating CXCR4 help the bacteria evade the immune response?

Nancy GoughThe authors found by adding fimbriae to monocytes, a kind of blood cell involved in responding to infection, that the fimbriae promoted an interaction between CXCR4 and the Toll-like receptor TLR2 that I mentioned before.

The authors thought that this would increase signaling by TLR2, because fimbriae are known to promote the interaction between TLR2 and other receptors, such as CD14, and these interactions increase TLR2's activity. Surprisingly, the authors found, instead, that when the fimbriae promoted the interaction between CXCR4 and TLR2, signaling by TLR2 appeared to be inhibited.

John FoleyHow did they know that TLR2 signaling was inhibited?

Nancy GoughWell, when the authors added an antibody that blocked CXCR4 and then exposed the cells to the fimbriae, the cells had a much larger activation of NF-κB. NF-κB is a key transcription factor involved in mediating proinflammatory responses, and it is normally activated by TLR2.

In addition to a larger proinflammatory response, the production of the immunosuppressive cytokine interleukin-10 was lower when CXCR4 was blocked by the antibody before the fimbriae were added.

John FoleyWere the fimbriae interacting directly with either of these two receptors, or were they causing an indirect effect?

Nancy GoughWell, the fimbriae bound directly to CXCR4. The authors showed that CXCR4 was the direct target of the fimbriae by transfecting CXCR4 into a cell line that lacks CXCR4 and showing that only the transfected cells bound to the fimbriae.

John FoleyWere the authors able to determine how the interaction between CXCR4 and TLR2 inhibited TLR2 signaling?

Nancy GoughYes, they were. It appeared that the fimbriae activated CXCR4 because exposing cell lines to fimbriae produced an increase in the concentration of cyclic AMP and increased the activity of protein kinase A, which is activated by cyclic AMP.

If protein kinase A activity or the increase in cyclic AMP was blocked, exposing the cells to either the fimbriae or the intact bacteria stimulated a larger activation of NF-κB than was observed if CXCR4 signaling was intact. Recall that activation of NF-κB is a mark of TLR2 signaling.

John FoleyMost of what you have described are experiments involving the isolated fimbriae. Did the authors show that this CXCR4 interaction was relevant for cells exposed to the bacteria?

Nancy GoughYes, they did. The authors performed some experiments with mouse macrophages that were infected with P. gingivalis. Mouse macrophages use a nitric oxide pathway to kill the invading bacteria. When CXCR4 was blocked with an antagonist, nitric oxide production was greater and the number of viable bacteria was decreased, suggesting that CXCR4 signaling inhibits the cell's response to the infection.

John FoleyWhat about in live animals?

Nancy GoughCXCR4 was important in vivo, too. The authors performed experiments with mice infected with P. gingivalis. These infected mice showed enhanced clearance of the bacteria when CXCR4 function was blocked.

John FoleySo, it sounds as though disrupting this CXCR4-fimbriae interaction or interfering with CXCR4 signaling may be one approach for treating periodontitis.

Nancy GoughYes, that certainly seems possible.

John FoleyThanks for talking about this interesting research.

Nancy GoughYou’re welcome.

John FoleyThat was Science Signaling editor Nancy Gough talking about research that describes one way that P. gingivalis evades the immune system. The research article was by Hajishengallis and colleagues (1) and titled, “Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function.”

As mentioned at the beginning of the Podcast, CXCR4 is an important mediator of chemotactic responses. In the September 16th issue of Science Signaling, there was a research article about CXCR4 (3). The natural ligand for CXCR4 is stromal cell-derived factor or SDF-1 and recognition of SDF-1 involves a special posttranslational modification in the receptor called tyrosine sulfation. The Volkmann lab solved the structure of the extracellular domain of CXCR4 bound to a dimeric form of SDF-1, revealing insights into how sulfated tyrosines contribute to ligand binding. The dimeric SDF-1 also selectively stimulated calcium signaling by CXCR4, but did not promote chemotaxis. Dimeric SDF-1 actually inhibited chemotaxis stimulated by monomeric SDF-1. Read more about this research in the September 16th issue of Science Signaling.

We encourage you to check out the September issues of Science Signaling, which are free with registration. With the first issue in September, Science Signaling added original research to the weekly journal.

That wraps up this Science Signaling Podcast. If you have any questions or suggestions, please write to us at sciencesignalingeditors@aaas.org. The show is a production of Science Signaling and of AAAS, the Science Society. Our producer is Robert Frederick. I'm John Foley, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for joining us.


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