One goal of the young science of “Darwinian medicine” is to understand how infectious microorganisms might actually manipulate the host’s behavior to facilitate the microorganisms’ own transmission. This is nothing new to evolutionists—we have several examples of larger parasites, like flukeworms or fungi, making their hosts behave in a way that helps the parasite complete its life cycle—but it’s a phenomenon of evolutionary biology that is at once fascinating to contemplate, tricky to understand (what chemicals can a simple parasite produce that can affect the host’s brain or behavior?), and of potential value in treating disease.
Evolutionists have speculated, for example, that cold viruses leave you ambulatory because they have to spread by person-to-person transmission, while the malaria parasite makes you prostrate, because mosquitoes (their vehicle of transmission) are more likely to bite successfully when the victim is laid out and unable to slap the insect.
By “adaptive” in the title, then, I mean “adaptive for the malarial parasite”, which in this case is the the sporozoan Plasmodium falciparum—a protozoan. The parasite infects mosquitoes of the species Anopheles gambiae, and those parasites migrate to the mosquito’s salivary gland, from where they get injected into humans when mosquito bites. They then multiply first in the human liver and then in the red blood cells before being re-ingested by a subsequent mosquito bite. (That’s if they don’t first kill the human!) It’s essential for mosquitoes to bite humans because that’s the only way they can multiply both sexually and asexually and then spread from mosquito to mosquito. Without the infected mosquitoes biting, the parasite goes extinct. Ergo, any adaptation in the parasite that makes its mosquito host bite more readily will be an adaptive trait.
Falciparum malaria, as you may know, is the deadliest form of malaria, and virtually all malarial deaths are caused by this one sporozoan species (770,000 per year!) rather than by other forms of Plasmodium. At present 200 million people have the disease, which is one reason why the Gates Foundation has targeted eradication of the disease in the next decade or so. Such eradication can be achieved by eliminating transmission of the parasite between mosquitoes for three years, something that was achieved in the U.S. by 1951.
Here, from a Wiki Commons site, is a photo of a human blood smear containing P. falciparum gametocytes—the sexually reproductive stage of the parasite, The page notes that “At the peak of infection time, the infected person may carry up to 2 million parasites per microlitre of blood.” That is two million parasites per one-millionth of a liter of blood! I find that hard to believe.
Which brings us to the paper. In a report in the latest PLoS ONE (link and free download below), R. C. Smallegange and colleagues report a simple experiment: they looked at the feeding behavior of mosquitoes that were either uninfected or infected with P. falciparum. It was already known that another species of mosquito (Aedes aegypti) that carries bird malaria (P. gallinaceum) bit guinea pigs more readily when the insects were infected than when uninfected.
What Smallengange did was simply replicate this experiment with two changes: using human rather than guinea pig odor, and using mosquitoes infected (or uninfected) with P. falciparum. The “bioassay” was a nylon sock worn for 20 hours by a Dutch volunteer (a single male who had been shown to be the most attractive to mosquitoes among 47 volunteers exposed to the insects). The socks were put in a cage containing either infected and uninfected mosquitoes, and the landings of each type of mosquito on the sock were recorded (this was done blind, of course).
The results were clear cut: infected mosquitoes landed far more frequently on the sock when infected than when uninfected. Here’s the figure from the paper. No odor, no bites. With human odor, significantly more bites when the mosquitoes were infected than uninfected.
falciparum infected (red bars) An. gambiae s.s. females in response to no odor (left bars) or human odor (right bars). Error bars represent the standard
error of the mean.
I suspect that it would prove real on replication, although the authors should test this with odors of nonhuman animals as well. (It would also behoove them to repeat this experiment with more than one odiferous Dutchman, for the effect is, after all, supposed to be general.) If the result is replicable, it implies that the sporozoan parasite is doing something to the mosquito to make it bite more avidly. That, as I said, is to the parasite’s advantage.
If the parasite is indeed manipulating the mosquito to bite, how does it do this? We don’t know. As far as I know, in fact, in none of the cases of parasites manipulating hosts do we understand the biochemical/physiological basis of the manipulation. The authors report one study of the same mosquito, but infected with the rodent malaria parasite Plasmodium berghei, in which infected mosquitoes showed altered expression of 12 proteins expressed in their heads—including proteins possibly involved in the olfactory system. Smallengange et al. suggest that whatever the parasite is doing to the mosquito, it’s possibly doing it by changing the mosquito’s sense of smell, perhaps through changing how the olfactory receptor (OR) proteins bind to airborne stimulants.
It’s fascinating to contemplate how very simple organisms can induce complex behavioral changes in their hosts. It all goes to show the truth of the old dictum, “Evolution is smarter than you are.”
h/t: Gregory
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Smallegange, R. C., G.-J. van Gemert, M. van de Vegte-Bolmer, S. Gezan, W. Takken, R. W. Sauerwein, and J. G. Logan. 2013. Malariai infected mosquitoes express enhanced attraction to human odor. PLoS ONE 8:e63602 EP -.
Using the same methodology to test the efficacy of odor-masking sprays would seem to me to be a very good next step. I’d pay a lot of money for a result of 0 bites from 97 mosquitos over 3 minutes.
Does remind me of the recent reports about infecting malaria mosquitoes with Wolbachia bacteria, so that they cannot carry parasites any more.
I am interested how creationists would react to this.
This is yet another example of a phenomenon that has an elegant, parsimonious, rational, and testable evolutionary explanation; whereas for creationists it can only be that a sadistic god was so pissed after the “fall” that he set it up so that mosquitoes not only transmitted the malarial parasite, but had them bite more people when they (the mosquitoes) are infected than when they aren’t.
I’d think instead that it’s something a lot simpler, such as producing a ghrelin analogue.
Cheers,
b&
I just started to write a comment farther down about how the parasite could simply make the mosquitoes feel hungrier. Then I saw you beat me to it!
These results are pretty cool, but not definitive by any means. While folks often rag on psychology for sloppy methodology, it seems to me that the shortcomings Jerry points out in this study are pretty serious — there is no firm evidence that anything can be claimed beyond “infected mosquitos land more frequently on something that smells like one particular mammal.” As I understand it, the research doesn’t even show that bite frequency increased, merely landings.
I came to learn of this study via another outlet: http://www.improbable.com/2013/05/16/study-builds-on-ig-nobel-winning-smelly-feetmalaria-work/
It is distressing that, despite the fact that a winner of a “useless” science prize has been shown to have important health implications, American and Canadian politicians continue to push for limited science funding.
The Igs are humorous, yes, but by no means useless. They highlight research that makes you laugh…and then makes you think. And they’ve got lots of very prominent support from lots of Stockholm-variety Nobel laureates.
b&
I don’t have the reference to hand, but I think the manipulation of cricket and other orthopteran hosts by horsehair worms is pretty well understood biochemically. These are the parasites that “compel” the host to go near water, where the worm bursts out of the insect and completes its life cycle.
Another case with very good data on the mechanism is the manipulation of cockroaches by jewel wasps; Carl Zimmer has written about this (as have I). Here the wasp injects a neurotoxin into the brain of the roach, rendering it docile but still ambulatory, and then leads the roach to her burrow, where she lays an egg on it. The larvae feed on the roach when they hatch. A recent paper pinpointed the alteration in the cockroach’s nervous system.
Thanks, Marlene. Yes, the parasites compel the host to go near water, but do they know how they do that?
I didn’t know about the neurotoxin thing, but I’d like to know how it works to render the wasp docile but still mobile.
For the jewel wasps, a Nature News article summarizes the recent findings pretty well: http://www.nature.com/news/2007/071129/full/news.2007.312.html. Apparently the venom blocks octopamine in the roach’s brain. If you reactivate octopamine receptors, you reinstate walking. Cool.
The horsehair worm story is quite complicated, from what a short search reveals. Work out of Frederic Thomas’ lab has shown that the worms can alter several aspects of the host behavior; for example, “hairworm infection fundamentally modifies cricket behavior by inducing directed responses to light” according to a 2011 paper by the group in Behavioral Ecology.
Schistocephalus solidus affects momoamine levels in Stickleback brains http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1088756/
“a single male who had been shown to be the most attractive man among 47 volunteers exposed to mosquitoes” – what difference does it make to the bioassay that he is the most good-looking volunteer?! Anyway, as someone who has had malaria I wouldn’t wish it on anyone: ‘prostrate’ does not do the feeling you have justice.
I meant “attractive to mosquitoes”! I’ll fix it.
Damn – I hoped I could cite this paper as proof that I was attractive 🙁
A seemingly minor change of a complex system can result in major changes to the functioning of the system. A good example of an obvious corollary to “complexity can arise from simple starting conditions.”
But specific examples, like infectious micro organisms altering their hosts behavior to benefit their reproduction, are still really cool, amazing even.
It is indeed pretty hard to imagine 2 million parasites per microlitre, but it is true! There are about 4-6 million red blood cells per microlitre in a human. When you ask for a malaria smear to be done on a patient, the lab will typically report back on the “percent parasitaemia” – i.e. how many of the red cells have the malarial parasites within them. In severe cases it can be over 30-50%, which is compatible with the figures given.
The figure given shows the rarer gametocytes well, but to the right, half way down, you can see one of the ring forms within a red cell (it’s the red cell with the two dark blue dots inside). If you had, say, 30% parasitaemia, then 30% of those red blood cells would have the ring forms within them.
Isn’t that why malaria is so painful? All those parasites clogging up the plumbing?
Yeah, that’s one reason. When they invade the red cells they make them produce little protuberances with a parasite-derived protein on the tips of these protuberances. The protein makes the red cells stick to the vessel walls and stick to each other. This is probably so that the red cells don’t get carried to the spleen, where our immune cells would mop up the infected cells. But the effect is that they obstruct blood flow to the tissues which can cause the tissues to infarct (and get painful) in some cases.
Reportedly rabid dogs, are more aggressive than unaffected ones and certain viruses cause us to sneeze. Presumably these are all examples of evolutionary adaptations whereby the parasite modifies it’s environment.
I am probably imagining it, but people with colds always seem more anxious to shake hands than those without. 🙂
Poor Dutchman. At least now he can boast with scientific certainty “It’s always me who gets bitten!”
One thing that puzzled me about this behavior influence being adaptive for the parasite. There is no blood in the sock. In the real world, a mosquito will land as many times as she needs to get enough blood and then stop, whether she is infected with Plasmodium or not. At least, I would think so, because continuing to land on humans after getting enough blood would be pretty dangerous behavior. It would be interesting to repeat the experiment with mosquitos that were already full. If they keep landing after that, their behavior is pretty clearly being manipulated.
Excellent observation! It suggests “number of landings” (beyond 1) might be a poor indicator of the intensity of the adaptive behavior.
Your suggested modification sounds good, but it conflates the intensity of the “go to the human” urge with the background “well, i’m full; gotta go lay eggs now” urge; this latter urge is in opposition to the former, and if it’s normally more intense, the landing count would hide the effect of interest.
I think this problem is eliminated if you lay out 20 socks of which just one is stinky, release a hungry skeeter about a metre away, and count hits v misses on the stinky sock.
My father used to let mosquitoes get their fill if they had started, operating on the principle that they would remove some of their injected saliva. (Presumably making the procedure less painful. I don’t know about that, and I always go for the kill.)
A decent part of such mosquitoes do indulge in dangerous behavior, from ingesting so much they can’t fly well, over having trouble detaching a clumsy body without leaving parts of themselves (which may or may not be inconsequential to successful egg laying), to in fact killing themselves by splitting. I don’t have the statistics, but I think mosquitoes may well go to the top of the list of frequent Darwin Awards.
Thanks, very interesting!
Also, I’ve heard the “let it finish and extract it’s saliva” idea a few times myself. Hard to figure out how that would work, though. (Mechanically, for the mosquitoes, that is.)
Probably about as useful as the idea of sucking out the venom from a snakebite.
When annoyed by a mozzie at night in bed, I sometimes just wait for it to be close to my face and then inhale sharply through the mouth. It works, and I’ve swallowed/inhaled worse things.
I think the size of the blood meal is proportional to the number of eggs laid by the female and/or how well she provisions the eggs. So taking a big blood meal, even if cumbersome, has a selective advantage.
“Evolution is cleverer than you are” is not such an old dictum that its origin is lost in the mists of time (better known as Orgel’s second rule).
Except that the lack of citations in the wiki link weakens my assertion… This page traces it to Francis Crick quoted by Dan Dennett in Elbow Room (1984), which is probably where I first came across it (Crick explicitly attributed it to Leslie Orgel, which is where I first heard of him).
I like ERV’s take, which goes somthing like “parasites are smarter than you are”, meaning their invasive behavior fools your defensive behavior – on your own backyard. Besides making me think, it also captures some of the “neener neener” observation on creationism that I see your first link alludes to.
When checking that nyah nyah could be appropriate here, I stumbled over this excellent replacement:
“There’s an economic concept known as a positional good in which an object is only valued by the possessor because it’s not possessed by others. The term was coined in 1976 by economist Fred Hirsch to replace the more colloquial, but less precise “neener-neener”.”
Sheldon [Big Bang Theory show; my cursive]
Reblogged this on Mark Solock Blog.
This and other cases of parasite-mediated changes in host behavior also serve as goof examples of Dawkins’ extended phenotype concept. There is more than meets the eye when it comes to elucidating mechanisms of animal behavior.
Sorry I meant to write “good”