PodcastHost-Pathogen Interactions

Science Signaling Podcast: 16 February 2010

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Science Signaling  16 Feb 2010:
Vol. 3, Issue 109, pp. pc4
DOI: 10.1126/scisignal.3109pc4

Abstract

This is a conversation with George Hajishengallis about a Research Article published in the 16 February 2010 issue of Science Signaling.

(Length: 16 min; file size: 7.6 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_100216.mp3)

Technical Details

Length: 16 min

File size: 7.6 MB

File Format: mp3

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

Download Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_100216.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: Bacteriology, Cell Biology, Human Biology, Immunology, Microbiology

Keywords: Science Signaling, atherosclerosis, complement, gingivitis, innate immunity, periodontitis, Porphyromonas gingivalis, Toll-like receptor 2

Transcript

Host – Annalisa VanHookWelcome to the Science Signaling Podcast for February 16th, 2010. I’m Annalisa VanHook.

Today I’m speaking with George Hajishengallis, corresponding author on a Research Article published in the current issue of Science Signaling, about how the pathogen Porphyromonas gingivalis evades the immune system to cause infection. Dr. Hajishengallis spoke to me from his office at the University of Louisville School of Dentistry.

Interviewer – Annalisa VanHookWelcome, Dr. Hajishengallis.

Interviewee – George HajishengallisThanks for calling me.

Interviewer – Annalisa VanHookIn the paper that you’ve just published in Science Signaling, you focus on infection by Porphyromonas gingivalis. Before we talk about that organism specifically, how does the immune system become activated to fight an infection?

Interviewee – George HajishengallisWell, invading microbes are detected by specialized bac sensors or receptors of the so-called innate immunity. And this is a type of immunity we are born with and becomes activated very rapidly after encountering a pathogen. However, innate immunity is relatively nonspecific and usually one needs the other arm of immunity—the adaptive immunity—to clear an infection. Now, adaptive immunity takes several days to kick in, but it’s highly specific for the type of invading pathogen. But, let me stress here, however, that innate immunity is not simply a way to buy time before adaptive immunity gets going. And this is because innate immunity is a really ancient defense system with a long coevolution with microbes; in contrast, adaptive immunity, and its sensors or receptors, which have no clue whatsoever on the biological context of the encountered antigen. For this reason, the adaptive receptors would not know whether to respond or not to an antigen they meet. And this necessary information is provided by innate immunity, which in this way can instruct the adaptive immune response. No wonder, therefore, that successful pathogens which undermine host differences are target[ing] preferentially innate immunity.

Interviewer – Annalisa VanHookSo, it’s the innate immune system that first responds to a pathogen, and then the adaptive immune response to that pathogen will kick in.

Interviewee – George HajishengallisYes. But, it’s important for the pathogen – if they want to evade the host response altogether – to start working against the innate immunity.

Interviewer – Annalisa VanHookHow do most pathogens, then, evade the innate immune system?

Interviewee – George HajishengallisIf your pathogen aspires to make it and persists in the mammalian host, they have to sabotage at least one of three stages of immunity. One is detection – that is to prevent their recognition by the sensing receptors. Second is to impair activation of the immune response, for example by attacking signaling molecules that transmit information for infection in order to mobilize antimicrobial responses. And the third way is to interfere directly with the antimicrobial response itself, for example, to destroy or resist the action of host defense molecules.

Interviewer – Annalisa VanHookThe strategy is either to avoid being recognized, to avoid the signal that’s generated upon being recognized, or to avoid the consequences of being recognized.

Interviewee – George HajishengallisExactly. So, either of these three, or all three together, or two of the three would work. The more you do the better it is, but you don’t have to do all three in order to persist in the host.

Interviewer – Annalisa VanHookAnd in this paper you’re looking specifically at the role of complement receptors in the immune response. Could you explain what the complement cascade is, in terms of the innate immune response?

Interviewee – George HajishengallisYes. Traditionally, complement was perceived as simply as an antimicrobial enzyme system found in serum. But, now we know better. For example, we know that now that a complement crosstalks with other different systems and actually has an impact on both innate and adaptive immunity. The complement system can be triggered by antigen-antibody complexes or microbial products, and the ensuing complement cascade involves sequential activation and proteolytic cleavage of a series of serum proteins. This will lead to the introduction of active fragments that carry out several coordinated functions, which aim, of course, to clear pathogens. And probably the most well known is the C3 and the C5a anaphylatoxins, which stimulate the recruitment and activation of phagocytic cells. And these are cells that literally eat bacteria – that’s why they are called “phagocytic.” Other generated complement fragments, known as opsonins, promote the phagocytosis of bacteria. And still other activated fragments form a complex—a protein complex—that targets and directly destroys pathogens.

Interviewer – Annalisa VanHookAre the complement proteins made by, by the cells of the innate immune system?

Interviewee – George HajishengallisThey are made by cells of the innate immune system, like microphages, in response to pathogens, but they are also produced by the liver, and they’re made available in the circulation. So, anytime we have constitutive presence of these serum proteins in the serum, but they are not activated, they are in their inactive form. You have to activate the cascade in order for these proteins to generate active fragments to carry out effector functions.

Interviewer – Annalisa VanHookComplement proteins are around all of the time, and the cascade gets activated when a pathogen is detected by the innate immune system.

Interviewee – George HajishengallisExactly. I mean, as we speak our blood contains these proteins, but hopefully they are not activated because we are not invaded by pathogens. Complement is triggered every time we see a pathogen, and actually there are many molecules – like lipopolysaccharide, CpG DNA, zymozen – these microbial products activate both complement and Toll-like receptors at the same time. Some bacteria, however, they inhibit the complement cascade, and this is part of their defense, their evasion strategy. But, the normal way to respond is to have to the complement cascade activated when we have an invading pathogen.

Interviewer – Annalisa VanHookIn this current study that your group has just published you focus on the pathogen Porphyromonas gingivalis.

Interviewee – George HajishengallisYes, Porphyromonas gingivalis.

Interviewer – Annalisa VanHookThe name of this organism implies it has some association with gum disease, with gingivitis. Is this the bacterium that causes gingivitis?

Interviewee – George HajishengallisYes. Porphyromonas gingivalis – or simply P. gingivalis – as the name implies, are, causes inflammation of the gingiva, or gums. In its severe form, this disease is known as periodontitis, and its hallmark is inflammatory destruction of the bone that supports the teeth. This, of course, can lead to tooth loss. Moreover, P. gingivalis has been implicated in systemic inflammatory diseases. For example, this bacterium has been found alive in atherosclerotic plaque lesions and in lung abscesses. Let me say here that periodontitis is epidemiologically associated with atherosclerosis and oral aspiration pneumonia. And, in addition to that, there is recent evidence which suggests that P. gingivalis infection may prime the autoimmune response in rheumatoid arthritis.

Interviewer – Annalisa VanHookSince all of the diseases, or the disorders, that P. gingivalis is, with which it’s associated, are inflammatory in nature, it’s the immune response that’s causing the damage, not the bacterium.

Interviewee – George HajishengallisAbsolutely. That, that’s very correct, yes. And there is another kind of paradox because P. gingivalis is very specific when it tries to do immune evasion. It does not induce a wholesale immunosuppression, it’s very specific – it wants to block only those pathways that are going to eliminate it; it wants to keep open all other inflammatory pathways. And the reason is not because it’s mean and wants to do us harm—although this is what happens—it’s because it thrives on inflammation. This is an, its an autolytic bacterium – it needs peptides and hemin, which is a substance from the blood – which means that it needs the inflammatory fluid to get hemin because hemin is essential for growth. If there is no inflammation, it’s going to die.

Interviewer – Annalisa VanHookRight. It needs food.

Interviewee – George HajishengallisYes, exactly. So, it is, it is not in its best interest to stop inflammation altogether.

Interviewer – Annalisa VanHookYou focused on P. gingivalis because it does something that seems to be counterintuitive for an invading pathogen that wants to evade the immune system. So, what is it that P. gingivalis does that seems to be counterintuitive to ensuring its own survival?

Interviewee – George HajishengallisYes. P. gingivalis does indeed [do] an unusual thing. This bacterium proactively generates the complement of fragment C5a using an enzyme that mimics the action of the host enzyme that generates C5a. That does not make much sense, especially since this pathogen goes at great lengths to block the physiological complement cascade.

Interviewer – Annalisa VanHookWhile on the one hand it shuts down the complement cascade, it then produces one of the molecules that’s important for the complement cascade.

Interviewee – George HajishengallisYes.

Interviewer – Annalisa VanHookBut just this one molecule.

Interviewee – George HajishengallisYes. This is exactly what it does. For example, when it cleaves the C5, to generate C5a, very transiently it also generates the C5b, but it goes ahead and it completely destroys this C5b because if he leaves it intact this would start a smaller cascade, the terminal pathway, that will form the membrane attack complex. So, it kills this pathway; it leaves only C5a intact.

Interviewer – Annalisa VanHook…to stimulate the C5 receptor.

Interviewee – George HajishengallisYes. Why then does P. gingivalis specifically generate C5a – which, by the way, is the most potent complement fragment – it is like generating weapons for your enemy. And this is what actually intrigued us to undertake this study. And we found that P. gingivalis has a hidden agenda. Let me explain that. When P. gingivalis activates the C5a receptor together with another inflammatory receptor, the Toll-like receptor 2, the net effect, strikingly, does not promote P. gingivalis killing by phagocytic cells. This trick, however, would not work if the C5a receptor, or the Toll-like receptor 2, were to be activated alone. And there is more to it. This crosstalk between the C5a receptor and the Toll-like receptor that is instigated by P. gingivalis blocks specific functions that could eliminate this pathogen – it does not block all inflammatory responses, which are actually reinforced by this crosstalk. Does P. gingivalis like this? You bet it does – because this pathogen needs inflammation [to] survive. The inflammatory fluid brings nutrients, like hemin, which are essential for P. gingivalis growth. And as if this was not bad enough for us—the host that is—inflammation contributes to the destruction of the tissues that support the teeth.

Interviewer – Annalisa VanHookP. gingivalis makes this, this protein that activates the complement receptor, which then, which participates in crosstalk with the Toll-like receptor 2, or TLR2. Do these two pathways normally crosstalk in the immune system, or is this crosstalk only initiated in response to infection by P. gingivalis?

Interviewee – George HajishengallisYes. The concept of complement-TLR crosstalk, or Toll-like receptor crosstalk, is really a new concept. There have been only a few papers, actually very recent ones. And yes, there is crosstalk between not only C5a receptor but also this C3a receptor, with several TLRs and mostly with TLR4. And this crosstalk actually involves either synergistic interactions or antagonistic interactions. And the purpose behind – these are physiological crosstalks, okay – and the purpose behind this crosstalk is to coordinate the innate response to infection so it will reinforce responses that are needed to fight pathogens, but there are also antagonistic interactions to put a brake on the immune response, not to get out of control.

Interviewer – Annalisa VanHookHow does promoting that crosstalk benefit the pathogen?

Interviewee – George HajishengallisWhen P. gingivalis instigates this crosstalk – and by the way, it can directly activate both receptors because it can engage the TLR2 directly with its surface molecules, and it can generate at will C5a to activate C5A receptor; it does not rely on immunological means to get C5a; it can do it itself at will. And so, what happens – and this is what is striking about it – although its receptor is inflammatory on its own, it – both induce inflammatory signaling. When you have coactivation of these two receptors, or they’re brought together by P. gingivalis, the net effect is strikingly immunosuppressive, at least for one specific function – that is, the production of an antimicrobial enzyme, called iNOS, that produces a toxic substance nitric oxide, to which P. gingivalis is exquisitely sensitive. And P. gingivalis kills this pathway by this crosstalk.

Interviewer – Annalisa VanHookClearly, this is interesting from the point of view of the strategy of the pathogen, you know, how the pathogen evades the immune system. But, from studying the way that P. gingivalis evades the immune system, does this teach you anything about, about signaling in the immune system?

Interviewee – George HajishengallisYes. This is not just about P. gingivalis and periodontitis. We also learned something new about the innate immune system. So, when signaling pathways collide, you may have emergent properties. Indeed, the specific pathway that is triggered by the crosstalk between the C5a receptor and the Toll-like receptor 2 and culminates in the production of an antimicrobial molecule that would kill P. gingivalis, this pathway could not be predicted by considering the standard pathways activated by the C5a receptor or the Toll-like receptor 2 alone. These findings also tell us that successful pathogens may not have simply learned to attack the complement or the Toll-like receptor system separately, but to also instigate disarming crosstalk between the two systems. This is what is novel about this study.

Interviewer – Annalisa VanHookSo, essentially, you were able to use this pathogen’s strategy for evading the immune system to uncover a property of the innate immune system that wasn’t readily apparent before.

Interviewee – George HajishengallisExactly.

Interviewer – Annalisa VanHookIn addition to just learning something new about how the immune system functions, and getting back to P. gingivalis did you learn anything from this study that might help in treating or preventing infection by P. gingivalis?

Interviewee – George HajishengallisYes. That study was very helpful in this regard because if we block C5a receptor—and there are many ways for doing this; we have excellent small molecule inhibitors—then two good things will happen. One is that we will deprive P. gingivalis of an evasion strategy. In other words, by blocking the C5a receptor, then the killing of P. gingivalis will be greatly facilitated. And then second, by blocking the C5a receptor, we are going to inhibit inflammatory responses, where there were inflammatory responses that were not doing anything productive against the bacteria but actually contribute to the destruction of periodontal tissues. So, it’s like killing two birds with one stone.

Interviewer – Annalisa VanHookThank you, Dr. Hajishengallis.

Interviewee – George HajishengallisWell, thank you very much for having me. It was my pleasure talking with you.

Host – Annalisa VanHookThat was George Hajishengallis, corresponding author on a Research Article published in the February 16th issue of Science Signaling. That article is titled “Microbial Hijacking of Complement–Toll-Like Receptor Crosstalk” (1).

music

That wraps up this Science Signaling Podcast. If you have any questions or suggestions, please write to us at sciencesignalingeditors{at}aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook. On behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.

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