Archaea as human pathogens?

When I was in school, I was taught about the 5 kingdoms of life: Monera (all bacteria), and the eukaryotes: Protista, Fungi, Plantae, and Animalia. Since that time, there’s been a bit of a change in the organization. This is largely due to investigation of the Archaea (sometimes still referred to as “archaebacteria”). It was recognized that these organisms were so unlike bacteria (and of course, unlike the eukaryotes) that they deserved their own grouping. Therefore, the most common strategy currently employs 3 domains of cellular life at a level above the kingdom: Bacteria, Eukaryotes, and Archaea.

The archaea have received a lot of attention as “extremophiles:” the microbes that live in environments that have high salinity, very high or low temperatures, or other extremes that make the processes of life daunting. However, they also are residents of more benign locations, such as the human gut, mouth, and vagina. Despite this known association with humans, no species of archaea had ever been identified as a pathogen–until now.

A paper in the April issue of the Journal of Clinical Microbiology reports the identification of archaea in tissue from infected teeth. More specifically, within infected root canals of human teeth–a normally sterile site. Out of 20 cases examined, 5 were found to be positive for methanogens (a type of archae that produces methane as a by-product of metabolism). Because these organisms were found in a site where normal human flora are typically unable to gain access to, the authors suggest this supports the characterization of these archae as pathogens.

A key feature of pathogens that distinguishes them from non-pathogenic organisms is that they need strategies to allow them to gain access to sterile sites within the host; to accomplish this, they also must be able to evade the host’s myriad defenses. How many species of archae have these abilities? The paper notes two reviews published in 2003 that address this topic:

For instance, higher levels of breath methane (produced by methanogens) have been detected in patients with precancerous conditions (ulcerative colitis and colonic polyposis) and cancer of the colon. Cell wall structures of the archaeon Sulfolobus solfataricus have been demonstrated to exhibit toxic activity similar to that of lipopolysaccharides in mice and rabbits, indicating a genetically programmed immune response in those animals that recognizes archaea as potential pathogens. Furthermore, various toxin/antitoxin systems have been found in Methanococcus jannaschii, Archaeoglobus fulgidus, and haloarchaea. In addition, virulence genes for lipopolysaccharide biosynthesis and the tadA gene (e.g., required by Actinobacillus actinomycetemcomitans for nonspecific adherence) have been identified in archaea.

Though these data obviously aren’t conclusive regarding a role played by archaea in disease causation, they are suggestive of one, especially in conjunction with the findings in the current article.

If this is the case, then, how have we missed them until now? Mainly, we didn’t find them because we haven’t been looking. Archaea need special conditions for growth, so traditional culture methods won’t pick them up. Indeed, in this study they relied on a molecular method, detecting the presence of mcrA RNA (a gene which plays a role in methane production) and archaea ribosomal RNA. However, a previous study (Siqueira et al., see below) using a similar method failed to find any archaea in a similar type of infection. Because these organisms aren’t culturable by traditional methods, it’s difficult to know whether you’re missing the targets because they aren’t there, or because your system just isn’t working. Even a positive control in this case may not work 100%, as the positive control would be purified, single-species DNA or RNA, and clinical isolates have the potential to be mixed and may not be the exact same species the primers were designed for.

So, do archaea have the potential to be an emerging pathogen? Will we see more of these types of infections, in which archaea play a role? I think it’s likely. Perhaps they won’t be the sole agent (as they weren’t in this case–they were one part of a polymicrobial infection: an infection involving multiple infectious agents), but they may play a supporting role in the development of disease. Either way, it’s a fascinating line of research, shedding a bit of light on this largely unknown group of organisms that live within so many of us.

References

Cavicchioli et al. 2003. Pathogenic archae: do they exist? Bioessays. 25:1119-28.

Eckburg et al. 2003. Archaea and their potential role in human disease. Infect Immun. 71:591-6.

Siqueira et al. 2005. Searching for archaea in infections of endodontic origin. J Endod. 31:719-22.

Vianna et al. 2006. Identification and quantification of Archaea involved in primary endodontic infections. J Clin Microbiol. 44:1274-1282.

Comments

  1. #1 Scott
    May 17, 2006

    Wow…that puts a whole new spin on flossing and bad breath…

  2. #2 coturnix
    May 17, 2006

    I was waiting for this to happen. So many of them, so adapted to life in inhospitable places (like parts of our body) – I always thought it was curious that none of the Archaea were ever identified as pathogens, either in humans, or in other Eukaryotes (plants, fungi and animals all included).

  3. #3 Hank Barnes
    May 17, 2006

    Do Archae have to satisfy Koch’s Postulates before they are decreed to be pathogenic?

    Just askin’

    HB

  4. #4 Dave S.
    May 17, 2006

    Don’t keep us in suspense Hank….do they?

  5. #5 Tara C. Smith
    May 17, 2006

    Hank,

    I’ve discussed previously how Koch’s postulates have been refined and updated–and how they were invalid even in his own time. Do you need a refresher? Additionally, as I’ve mentioned several times, Koch’s postulates aren’t the only way to determine disease causation.

  6. #6 Hank Barnes
    May 17, 2006

    I’ve discussed previously how Koch’s postulates have been refined and updated–and how they were invalid even in his own time.

    Huh? Invalid in his own time? Did Koch know about this?:)

    Do you need a refresher?

    Nah, I’m still fresh:)

    Additionally, as I’ve mentioned several times, Koch’s postulates aren’t the only way to determine disease causation.

    Funny, how these mysterious “other” ways were not mentioned in your post.

    So, since That Girl, Dr. Smith, has singularly invalidated Koch’s Postulates, What ways would she go about demonstrating that Archae X does in fact cause Disease Y?

    Please note, your paper identifying Archae in rotting teeth, could equally signify that Archae is a consequence of said rotting teeth, not a cause.

    Of course, as an epidemiologist, you probably know this.

    Hank Barnes

  7. #7 Hank Barnes
    May 17, 2006

    Also, not to quibble, but your heading, says, “Archea”, but I think its “Archae”.

    Hank

  8. #8 Nick
    May 17, 2006

    One quick search on wikipedia reveals that Koch himself acknowledged problems with his postulates, modifying or even abandoning parts of them.
    Wikipedia

    Yes, Hank, I’d say he had some idea.

  9. #9 Paul Orwin
    May 17, 2006

    Wow Tara, i guess you really never read my blog :(. This is following up on some work David Relman did a few years ago.

    Archaea and Disease

    Hank,
    I hesitate to jump in here since you are a well known troll, but no, it is “Archaea”, at least among microbiologists. Every intro Microbiology student is taught the limitations of Koch’s postulates, so they understand that it is a very good rule of thumb, rather than an absolute law of nature. You are wasting everyone’s time with this silliness.

  10. #10 Sandra in Dallas
    May 17, 2006

    This may be a huge and ignorant jump, but could it be that HIV allows some Archaea to flourish and they have a role in full blown AIDs? If they have not been cultured for due to their atypical growth patterns, could they be a factor that we have totally missed?

    I won’t be offended if you tell me there’s no possibility, I’m not in a science field.

  11. #11 DDS
    May 18, 2006

    HB,
    The other ways are not quite so mysterious and I am sure Tara knows about them. They are called the Molecular Koch’s postulates and were first proposed in 1988 by Stan Falkow. These are also not perfect but they are an excellent complement to Koch’s original postulates. A recent review can be found here (http://www.nature.com/nrmicro/journal/v2/n1/abs/nrmicro799_fs.html)
    and an editorial here(http://www.nature.com/nrmicro/journal/v3/n12/full/nrmicro1311.html)
    and references therein.

    If you can’t access the full articles I’d be happy to send you a copy.

    D

  12. #12 Tara C. Smith
    May 18, 2006

    DDS–

    Indeed, I’ve discussed molecular Koch’s postulates with Hank before WRT HIV/AIDS, and I think I’ve even used that very Wikipedia link Nick posted as well.

    Hank, obviously I’ve not “singularly invalidated Koch’s Postulates”, nor is it my job to “demonstrate that Archae X does in fact cause Disease Y”. Indeed, I touched on what you mention:

    …identifying Archae in rotting teeth, could equally signify that Archae is a consequence of said rotting teeth, not a cause.

    And of course, it can. That’s why I discussed the uncertainty of archae as a pathogen–do they invade on their own? Are they a “bystander” that can crash the gate after another microbe starts to swing it open? That’s also why I emphasized that this was a polymicrobial infection–archae aren’t there alone. So–again, as I mentioned–it’s not yet certain that these are the “root cause,” if you’ll pardon the pun, of the dental infection–but it seems they are, at minimum, a contributor to the disease development.

    [and indeed, the correct spelling is actually "archaea"; as regular readers know, I'm not exactly a spelling nazi and tend to be a bit careless sometimes. In this case, I had 2 different spelling versions in addition to that one--archae, leaving off the last "a", and archea, leaving out the second "a". Lesson: don't take spelling lessons from me. :) ]

    Paul–you’re making me feel bad! To be fair, the post was from 2004–I read the new stuff, but haven’t surfed the archives. I included it in Animalcules since it was a nice compliment to this post.

    Sandra–that’s a good question. Searching PubMed for “HIV, archaea” brought up over 600 citations, but none of them look to be about the right topic. Searching “HIV, methanogen” didn’t bring up any. Perhaps someone else will know if this is an ongoing line of investigation somewhere.

  13. #13 Tara C. Smith
    May 18, 2006

    (Side note for anyone interested: previous thread where Koch’s postulates–and their limitations–were discussed.)

  14. #14 biosparite
    May 18, 2006

    As a non-blogger and a relative newbie at commenting on blog topics, I with some sense of temerity post a comment a bit off-topic: see the current e-edition of NATURE freshly arrived in in-boxes today re the obsolete usage “prokaryote” and the closer evolutionary relationship of the eukarya to archaea than to the bacteria. I point this out since we are already talking about archaea in another context. If I have violated some protocol in going off-topic, please be gentle with me.

  15. #15 DDS
    May 18, 2006

    Tara,
    I haven’t learned enough about HB to determine whether he is just dense or likes to appear dense to provoke a reaction.

    Biosparite,
    I just read Pace’s commentary. In the end I guess I don’t care what happens. I’ll probably continue to use the term prokaryote out of habit. Maybe some day the word will fall out of favor. But, I still think it provides a valuable distinction between Euks (big and have a nucleus) and Bacteria/Archaea (small, no nucleus). (Yes, I know there are big proks and small euks. No definition is biology is ever perfect). Whether it has phylogenetic utility does not concern me that much. I think the bigger phylogenetic question that needs to be answered is what (if anything) makes a bacterial genus/species? Maybe Linnaeus’ system (http://en.wikipedia.org/wiki/Carolus_Linnaeus) just doesn’t work well with those little prokaryotic critters.

  16. #16 Hank Barnes
    May 18, 2006

    A Wake-Up Call for Science Faculty by Dr. Alberts is highly recommended for some of you folks.

    HB

  17. #17 Tara C. Smith
    May 18, 2006

    biosparite, I actually have a post on that in my drafts–just been too busy today to get to it.

  18. #18 DDS
    May 18, 2006

    HB,
    It is an interesting read. It follows a long line of efforts to revamp the undergraduate and high school (as well as med school) science curriculums. Bruce Alberts has certainly been a leader in the effort. Others have provided specific ways of including more hands-on science in the class room. (http://www.sciencemag.org/cgi/content/summary/sci;304/5670/521)

    The major problem is of course money$$$$$. Jo Handelsman said it well:

    “Finally, the reward system must be aligned with the need for reform. Tenure, sabbaticals, awards, teaching responsibilities, and administrative support should be used to reinforce those who are teaching with tested and successful methods, learning new methods, or introducing and analyzing new assessment tools.”

    At most research Universities bad teachers who have grants can get tenure. Outstanding teachers who don’t have grants don’t get tenure. Until this is changed, not just in words but also in practice, teaching will be an after thought.

    Sad…Sad..Sad..

    D

  19. #19 iGollum
    June 21, 2006

    Side comment (non-Koch-related) on the paper, haven’t read it but looking at the excerpt posted here… I’m a little perplexed as to why the authors cite the existence of toxin-antitoxin systems in these beasties as supporting the archaea-as-pathogens hypothesis (which I’m not against, btw). One of my colleagues works on T-AT systems (so my knowledge is only second-hand) and my understanding was that they’re interpeted as being either maintenance systems for plasmids, or part of a quorum sensing/ apoptose-like mechanism for the colonies, but not thought to be involved in pathogenesis towards a host. Anyone care to enlighten me on this point?