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Fighting Malaria with Mosquitoes

Malaria researchers learn to hijack mosquitoes' immune tricks for good
by Kurt Wong
24 January 2007 Comments 8 Comments

Fighting Malaria with Mosquitoes
Image: CDC Public Health Image Library
Anopheles mosquitoes transmit malarial sporozoites while obtaining a blood meal.
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Flu season is here. And while our human immune systems battle the winter onslaught of sniffle-causing viruses, another immune system on the opposite side of the globe is fighting the good fight. Its opponent: malaria, a parasitic infection spread by a nefarious vector, the Anopheles mosquito.

Mosquitoes’ own immune systems are more powerful than once thought, a new study in the journal Immunity shows. If properly harnessed, these immune mechanisms could help reduce the transmission of malaria, a disease which claims more than one million lives each year.

Cécile Frolet and her colleagues at the Institut de Biologie Moléculaire et Cellulaire in Strasbourg, France, manipulated the NF-kB gene in the gut of the mosquito, where the malaria parasite first takes up residence. NF-kB has been championed as a master immune gene, playing an integral role in switching on pathogen-fighting responses. In mosquitoes, NF-kB activates several genes that have been implicated in killing parasites, including Plasmodium, the parasite that causes malaria.

When Frolet silenced the NF-kB gene (using the Nobel Prize-winning technique known as RNA interference), the mosquitoes were unable to make the molecular factors they needed to kill the incoming parasite. These disarmed mosquitoes became more susceptible to infection and hosted more parasites in their guts. On the flip side of the experiment, mosquitoes with boosted NF-kB production made higher amounts of anti-parasitic factors, and their immune systems completely stymied parasite growth.

This study marks a big step in the possibility of using molecular mechanisms in the mosquito to kill the parasite before it ever has the chance to make it back into a new host. Indeed, Frolet and her colleagues demonstrate that by manipulating a single gene, they can achieve great responses against the malaria parasite.  In a world with ever-increasing drug-resistant parasites, learning how to harness such potent immune mechanisms may just be the next step in malaria control.

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Couple this with a low likelihood of being infected (in the wild around 5% as a generous approximate), then the large majority of mosquitoes would pay the cost of high NF-kB production without the benefit of not being infected (because they aren't infected!).
Posted on 3/8/08 at 1:34 PM by

Thanks for spreading this out, i think people should be well informed when it comes to malaria and diseases like this one.
Posted on 7/31/07 at 8:07 AM by

Kurt,

Perfect. Figured it was the Hurd stuff you were talking about. I happen to know Rob Anderson. He's a clever fellow. I can see why you linked the Anderson paper, although I've never interpreted it that way before. It suggests that there is adaptive manipulation by the Plasmodium on the mosquito, and I guess you're treating this as an apparent cost.

You've actually got me thinking quite a bit about the GMed mosquitoes. And getting me thinking is an amazing thing... I like to turn my mind off most of the time.
Posted on 1/28/07 at 5:04 PM by

TinyBabyRobot: What you're saying about the GMed mosquito fitness is indeed the common belief (*especially* because of the use of lab strains, which after years of inbreeding are definitely different from the wildtype). But it need not be the be-all-end-all! There is some research out there trying to find a way to tie malaria resistance to another, more necessary trait (to create a "drive mechanism" as they seem to call it in the literature).

Some references for you (and everyone else). I hope you're able to track them down without the fancy online journal proxies provided by my university:

On the cost of infection (being equal to that to the cost of resistance):
Hurd H et al. (2006). Evaluating the cost of mosquito resistance to malaria parasites. Evolution Int J Org Evolution. 59: 2560–2572.
LINK: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16526504

On malaria killing infected mosquitoes in the field:
Anderson RA et al. (2002). Plasmodium falciparum sporozoites increase feeding-associated mortality of their mosquito hosts Anopheles gambiae s.l. </i>Parasitology.</i> 120:329-33.
LINK: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=10811273

And a nice review on the GM mosquitoes:
Riehle MA et al. (2003). Towards genetic manipulation of wild mosquito populations to combat malaria: advances and challenges. J Exp Biol. 206:3809-3816.
LINK: http://jeb.biologists.org/cgi/content/abstract/206/21/3809
Posted on 1/28/07 at 10:51 AM by

Hi Kurt,

Cool stuff.

I'm aware that there is some research showing a reduction in fecundity and survivorship with Plasmodium infection, but this is mostly linked with a high number of oocysts not often found in the wild. I haven't encountered "in the wild" accounts of fitness reductions. I wouldn't be surprised because, as I stated in my previous comment, nothing is free. There's bound to be some costs due to infection, but the problem is that they may be negligible.

With respect to the mathematical modelling, if you're looking at an evolutionarily static picture of the mosquito population, then the basic reproductive ratio might drop (in these models), but my suggestion is that in a game setting, the GMed mosquitoes just wouldn't be around long enough to make a difference. That's the problem that all of these GM approaches seem to come up against. Couple this with the fact that most of the genetic research is done on lab colonies that are already deviated from the wild-type and it becomes even more difficult for these mosquitoes to compete.

Also, out of interest, what's the paper showing that "resistance may be just as costly as being infected"? (and the one showing that the fitness of infected mossies drops in the wild too?)
Posted on 1/28/07 at 4:51 AM by

Intriguingly, there have been several reports of reductions in fecundity and longevity of mosquitoes infected with malaria, both in the lab and in the field. Indeed a recent study looking at malaria-resistant mosquitoes claim that resistance may be just as costly as being infected.

We also know from mathematical modelling on vaccines that getting infections below a threshold level in the population can basically stop transmission all together. Thus it may not be necessary to replace the entire mosquito population with an pumped-up superbug; we just enough of the parasite-killing mosquitoes out there so that the number of infections falls below that threshold.

But much research needs to be done on all aspects of these ideas. Sadly, there's not enough money to share between the vaccine candidates and the worthwhile research in these fields.
Posted on 1/28/07 at 1:35 AM by

That's a very interesting comment. I love the evolutionary biology angle. It makes an interesting story even more so, in my opinion. Thanks!
Posted on 1/26/07 at 8:49 PM by Hugh Powell

The problem is that mosquitoes don't seem to incur much fitness cost when infected with Plasmodium, the parasite that causes malaria in humans. They don't seem to live any shorter; they don't seem to lay fewer eggs. And in the case of Plasmodium, it only takes 1 or 2 oocysts to make a mosquito eventually become infectious to humans. If turning the NF-kB production up incurs an energy cost (and it should because nothing is free), this has to outweigh the cost of being infected. It's unclear that it would.

Couple this with a low likelihood of being infected (in the wild around 5% as a generous approximate), then the large majority of mosquitoes would pay the cost of high NF-kB production without the benefit of not being infected (because they aren't infected!).

The long and short of it is, the GM'd mosquitoes would most likely get schooled by the wild-type mosquitoes.

*sigh* So many problems to think about... great write up though!
Posted on 1/26/07 at 6:46 PM by

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