Parasites as Neuropharmacologists

i-bc48e55e4e6b67fbdcb6558ff409e243-toxoplasma march.jpgReports are coming out this morning on a new study on one of the Loom's favorite organisms: Toxoplasma gondii, the single-celled parasite that lives in roughly half of all people on Earth and has the ability to alter the behavior of its host. I reported on the research last June in the New York Times, when the Stanford researchers reported their results at a scientific conference. It's nice to finally get the results on paper, though.

The study is a fine example of an underappreciated part of science: replication. In 2000 British researchers carried out a study in which they put healthy and Toxoplasma infected rats in an outdoor enclosure and watched them nose around. They added odors to some of the corners of the enclosure; sometimes the odor of rats, sometimes of rabbits, sometimes of cat urine. They found that healthy rats were deeply affected by the scent of a cat, becoming less curious. Parasite-infested rats showed no fear. They proposed that the shift in behavior was an adaptation of the parasite for getting into its final host--cats. (I included a description of this study in my book Parasite Rex.)

It was a remarkable result, but even remarkable results may not be so significant as they seem at first. They need to be replicated by other researchers. That's what the Stanford team has now done. They set up an enclosure, set both rats and mice loose in it, and observed a significant difference between infected and parasite-free hosts. The animals were actually attracted to the smell of cats. The Stanford team went beyond mere replication, however. They took a closer look at how the parasites manipulate their hosts.

For example, they found that even though the hosts lost their fear of cats, they still had normal anxiety in other respects, and could learn to become frightened of things. This is intriguing, since innate fears (such as the fear of cat urine) is the product of many of the same neurological circuits that produce learned fear and anxiety. Toxoplasma is particularly fond of living in the brain, where it forms cysts. The researchers mapped the parasites in the brain by adding a light-producing gene to them. As the parasites moved through their hosts, the light leaked out, and the scientists could photograph their journey (see the illustration above). They found that an unusual number of Toxoplasma ended up around the amygdala, a structure in the brain that's important for fear responses. (When the paper goes online this week, it will be here.)

While this is all extremely cool, scientists still have a lot to learn about Toxoplasma. Some recent research on the history of Toxoplasma doesn't fit comfortably with an image of the parasite as always trying to get its hosts into the jaws of cats. It's only in cats that Toxoplasma can reproduce sexually. Two parasites mate and their offspring--egg-like cells called oocysts--carry a mix of their genes. But Toxoplasma can also reproduce like a clone, splitting in two, either in cats or outside them. The variation in genes from one Toxoplasma to another records the history of the parasite's reproduction. Cloning creates lots of parasites that are almost identical, genetically, while sex mixes them up in distinctive ways.

It turns out that most Toxoplasma in North America and Europe belong to three lineages that share a common set of parental strains that lived 10,000 years ago (nicknamed Adam and Eve). Once those three lineages emerged, they exploded. But they show little sign of sex. For the most part they just cloned themselves. It's not clear whether getting into a cat was all that important to the reproductive success of these dominant strains. (The other strains of Toxoplasma elsewhere in the world have yet to be studied closely.) It's possible that Toxoplasma's host manipulation is an ancient adaptation that's become a bit obsolete in modern strains, or perhaps it evolved thanks to the slight reproductive edge it gives over the course of many generations. (Sexual reproduction from time to time may be essential for the survival of a lineage.)

Despite these uncertainties, the new study certainly adds more weight to the notion that Toxoplasma has unconsciously figured out some key features of the mammal brain--features of fear and drug delivery that we don't yet understand. Just like wasps that perform brain surgery, these are parasites worth learning from.


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Whoa! That's genuinely surprising.

I guess it goes to show that as much as the world's changed, from our perspective, in the last 10,000 years -- for example, oh, that entire "civilisation" thing -- the life of toxoplasma has been remarkably consistent.

So I guess there's two things to draw from this. First, that toxoplasma is amazingly successful. Second, they target an amazingly successful host, i.e. rats. If anything, that ties into the development of civilisation that I mentioned above. We humans have gradually created an environment that is simply perfect for rats, so why would either the rats or their incredible parasites bother to change in all that time?

Joshua--I should have pointed out that Toxoplasma can infect any mammal or bird. Awesomely versatile. So rats may not be the secret to their success.

>a common set of parental strains that lived 10,000 years ago

Would this time relate well to the time that cats were first domesticed, following the availability of bulk grain from agriculture? Domestication brings many unrelated cats together for social contact and would allow greater spread of toxoplasma.

Edit: "perhaps it have evolved"

By Brian Baker (not verified) on 03 Apr 2007 #permalink

Actually, Carl, I suppose that in itself goes a long way to explaining the success of Toxoplasma.

It would be interesting to know when that ability to survive in hosts other than its two first choices (rats and cats) developed and whether that correlates with this evolutionary sweet spot indicated by this research.

Toxoplasma gondii is an incredible example of evolution in action. I'd be interested to know the distribution of the infection in the US by state. We read that Korea has a low infection rate and Brazil a high one. Do US States have a similar variance?

Just finished P-Rex. What a read. I hadn't the remotest notion. Thanks.

I set down the book and found your blog. Looking forward to more scientific surprises...

This fascinating story gets better and better all the time.

Recently, there was a post on this subject at Neatorama:

I felt the need to reply to one of the comments there with a speculation on the evolution of such specialized brain localization. My guesstimate was that the parasites may target themselves to different tissue types by binding to tissue-specific markers.

Some years ago (six? seven?), an experiment was done in which filamentous bacteriophage were used to create a library of random peptide motifs that were "displayed" on their coat protesin. Each virion would express a different motif. This "phage display library" was then injected into the bloodstream of a mouse. After some incubation, different organs were taken, and bacteriophage were recovered from them. The bacteriophage population found in a particular organ was presumed to be enriched for phage that display peptides that confer tissue-specific localization.

After successive rounds of clonal isolation, propagation, selection by injection into more mice and harvesting; clonal isolates were found that could be targetted to specific tissues. The authors proposed that this type of targeting might be used to deliver drugs to specific organs or tissues; or even deliver drugs to tumors for chemotherapy.

So I wonder if there is any evidence of this kind of tissue-targeting in T. gondii. Phage display library enrichment is a laboratory-based evolutionary process, and is illustrative of the way that a parasite might evolve the kind of characteristics we are seeing now in Toxoplasma.

By Daniel Kim (not verified) on 15 Apr 2007 #permalink

Where did you run across the claim that most humans harbor Toxoplasma? As I understand it, during the period when pregnant women were routinely checked for Toxoplasma antibodies, positive results were not that common, even for lifelong cat owners.