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Infectious diseases

Turning the tables on parasites

Avian flu, whooping cough, malaria... these diseases all have something in common: they are caused by pathogens that attack people's organisms. Researchers at Gémi in Montpellier study the interactions between these parasites and their hosts. Their goal is to find new ways of eradicating the infectious agents and the diseases they cause.

insecte

© P. Goetgheluck

Manipulated by its parasitic worm, this cricket has jumped in the water. The worm then exits the body to continue its life cycle.


 

 

Pathogens don't think. They have not deliberately decided to harm us,” says François Renaud. That might seem like an argument in defense of viruses, bacteria and other disease-causing organisms. But the new director of the Laboratory of Genetics and Evolution of Infectious Diseases (Gémi)1 in Montpellier sees it another way: Pathogens are living organisms; they are subjected to the forces of evolution and in their own way, vastly contribute to the earth's biodiversity.

 

grenouille

© F. Thomas/CNRS Photothèque

A parasitic worm manages to escape this predatory frog even after its host was ingested.


Studying parasites with this in mind has helped researchers explore new strategies for combating infectious diseases. This type of research is essential at a time when avian flu is a major cause for concern, AIDS is devastating entire populations, and diseases once thought to have been eradicated are re-emerging. This is why Gémi, one of the few CNRS/IRD joint research units, has an edge for studying a variety of infectious diseases, “because it combines fundamental and applied research for sustainable development,” Renaud explains.

Renaud heads a team of thirty-odd researchers, PhD students, postdocs and a dozen lab technicians. He points to the several buildings that Gémi occupies, all interconnected by small Japanese gardens. “Pathogens use living organisms, including human beings, as an ecosystem. But their disease-causing capabilities are not a constant and depend entirely on the parameters of the ecosystem. In order to combat the most devastating among them, we focus on three essential mechanisms which are part of their evolution: entrance into the host, reproduction and transmission.” However, “the best parasite is not necessarily a dead one. That is, unless they are all dead. The problem is that if we kill off some parasites completely, others will have free reign to increase their virulence. It's a matter of finding the right balance.” Plasmodium falciparum, the infectious agent that causes malaria, provides a good example. Researchers know that the presence of intestinal worms reduces the virulence of Plasmodium. Another example can be found in industrial agriculture: “By concentrating large numbers of livestock, poultry, sheep, etc., into a limited area, a sort of biological reactor is created. If a virus adapts to one of the animals, it will contaminate them all. They will all be wiped out.”

 

Genetic diversity–that of people and their parasites–is just what Anne-Laure Bañuls studies: How does their respective gene variability act on the virulence of a parasitic disease in developing countries? In collaboration with local physicians, she is studying Chagas disease, which kills several thousand people each year in Central and South America. She is also interested in visceral leishmaniasis, a fatal disease found in India.

 

Another way of studying, understanding and hence combating parasites is to crack open the secrets of “parasitic manipulation.” The best-known case involves liver flukes. They push ants, obligatory intermediate hosts, to climb to the tips of grass leaves, where they will be more at risk of being eaten by sheep. Once eaten, the parasites take up residence in the sheep's liver. Frédéric Thomas at Gémi studies the case of crickets infected by horsehair worms and subsequently driven to suicide. “During the larval stage, the worms are obligatory parasites, but when they mature they are free-swimming and absolutely need water to survive.” So how do they manage to force the crickets to take the fatal plunge? Quite simply by communicating with them via secreted molecules. Thomas and his team have analyzed the proteome2 of the crickets and their parasites before, during, and after the “suicide.” They have demonstrated that the worms produce neuroactive mimetic molecules directly into the cricket's central nervous system, thus generating the host's fatal attraction to the reflection of light from the water's surface. More recently, they showed how the worms are able to escape their host even after being eaten by a predator (by climbing up the predator's digestive tube and exiting at the mouth).3

 

There are countless examples of parasites hijacking their host's metabolism. People infected with malaria experience a change in body odor once thought to be indirectly due to the physiological problems caused by the infection. But this change in odor has a very specific purpose: it attracts mosquitoes, thus enhancing the parasite's chances of being transmitted to other hosts.

Renaud's team has recently published another important finding on the reproductive cycle of this parasite.4 Plasmodium falciparum reproduces in the stomach of female mosquitoes. When a female mosquito bites an infected person, it ingests a number of parasites which end up in the mosquito's stomach, together with other parasites from other infected people. There, the parasite may either mix its genes with another Plasmodium or “clone” itself. Whatever mode of reproduction is chosen, the egg evolves into an oocyst.” Through a meticulous process, the scientists at Gémi have extracted and analyzed oocysts from the stomach of mosquitoes. They showed that one in four gametes (reproductive cells) fuses with a gamete coming from the same individual organism, meaning that 25 % of them are self-fertilized. “Such a high number overturns the generally accepted theory that alleles5 are randomly mixed in regions with a high incidence of the disease,” Renaud asserts.

But this goes beyond reproduction, as parasites also affect the host's behavior to increase virulent transmission. Once inside the mosquito, Plasmodium increases the mosquito's appetite, driving it to feed more frequently and thereby increasing its chances of being transmitted to another host.

 

If understanding a parasite's strategy for being transmitted is crucial, so is understanding how a disease spreads through a population. Jean-François Guégan addresses this topic by studying the temporal and spatial dynamics of parasites and infectious diseases. In simple terms, the question is when, how, and with what frequency do infectious diseases develop and spread? To answer that question, he has turned to work published by British researchers who have used epidemiological data to track the appearance, frequency, and localization of cases of whooping cough and measles across England. This study has revealed that epidemics recur in a wave pattern with regular intervals every two years in the case of measles, and every three and a half to four years in the case of whooping cough. Each epidemic is followed by a period of relative remission, although they discovered that cases of the disease still occurred in particular source areas of recontamination, even between epidemics.

 

coqueluche

In the Niakhar region (Senegal), the Toukar village (large red dot) is the source of retransmission of the bacterium responsible for whooping cough to the rest of the district.


“We did the same work in Senegal in the Niakhar region. This is a very arid and poor region where we could investigate whether the sanitary and socio-economic conditions played a role in the regular recurrence of the disease.” The answer appears to be no, since the dynamics of occurrence and transmission for both diseases were similar to those in England. Efforts to improve sanitary conditions are essential, but they are not the only key to curbing the spread of the diseases. Guégan believes that vaccinations would have a greater impact if they were carried out during periods of relative remissions, which is not the current practice. The novel approach developed at Gémi translates into a variety of unprecedented options to combat the spread of infectious diseases. Luckily, the researchers have an advantage over the accursed parasites: By studying the way they infect and manipulate hosts for acute transmission, scientists are now in a better position than ever to turn the tables back on them and curb the spread of major killers like malaria, which to this day,  takes a life every thirty seconds in Africa.

 

Julie Coquart

 

 

THE IMPORTANCE OF MODELING

 

The team of Yannis Michalakis is developing approaches to studying the mechanisms of the co-evolution of hosts and parasites. Sylvain Gandon, a researcher with the group, and British colleagues have shown that vaccines that diminish the risk of infection or transmission can also reduce virulence, while vaccines that diminish the rate at which parasites multiply can favor the emergence of more virulent strains.1 This theoretical approach may help evaluating the long-term effects of a vaccination program and identifying the best vaccination strategies.

J. C.

1. A.D. Morgan et al., “The effect of migration on local adaptation in a coevolving host-parasite system,” Nature. 437 (7056): 253-6. 2005.

 

Notes :

1. CNRS/ Institut de recherche pour le développement (IRD) / Université de Montpellier-II joint lab.
2. Total set of proteins present in a cell at a given time.
3. F. Ponton et al., “Parasitology: parasite survives predation on its host,” Nature. 440 (7085): 756. 2006.
4. F.G. Razakandrainibe et al., “Clonal population structure of the malaria agent Plasmodium falciparum in high-infection regions,” Proc Natl Acad Sci. 102 (48): 17388-93. 2005.
5. Different forms of the same gene. Alleles have the same chomosomal locations.


Contacts :

François Renaud
Génétique et évolution des maladies infectieuses,
Montpellier.Francois.RENAUD@mpl.ird.fr


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