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Project
Evolutionary potential of the human parasite Schistosoma mansoni in a changing world
The human helminth parasite Schistosoma spp. lives in the blood vesselsof over 200 million people in Africa, Asia and South-America. The most serious infections are found in children and adolescents who eventually become physically and intellectually compromised, while people who have been infected chronically may develop liver damage, kidney failure or bladder cancer. Despite the availability of a cheap and effective drug, the disease has been largely neglected compared to other more deadly diseases such as HIV/AIDS and malaria, both in terms of disease control andin terms of scientific research. Remedial action is therefore needed togain insight into the distribution of these parasites at both a local (among humans and villages) and a global geographic scale (across regionsor continents). It is essential to understand the factors and dynamics that shape transmission and the impact of selective pressures such as drug treatment. This will provide a theoretical framework that could represent a starting point for better disease control.
In this thesis we performed a population genetic study to reveal the distribution of Schistosoma mansoni</> parasites in the basin of the Senegal River (West Africa). Molecular markers such as microsatellites or single nucleotide polymorphisms serve as ideal tools to track the transmission of parasites and infer their ancestry. However, parasite worms cannot be used asa source for DNA as they are inaccessible within the human blood vessels. A protocol was therefore optimized that allowed the sampling, DNA-extraction and molecular analysis based on low quantities of DNA obtained from individual larval parasites (chapter 2). This optimization was an important first step that enabled us to perform multiple analyses on the same individual parasite with low genotyping error rates.
The case study in Northwest Senegal represents one of the most intense epidemic fociof S. mansoni.</> The parasite invaded this area in 1986 after the construction of two dams on the Senegal River. Parasites were obtained at four time points over a period of 14 years (1993-2007) and from several regions (Northwest Senegal, Southeast Senegal and Mali) to study the nature of the S. mansoni</> epidemic (chapter 3). Typing of nuclear and mitochondrial markers revealed that parasites from Northwest Senegal have a West-African origin, that they harbor moderate to high levels of genetic diversity, that they increase in population size and that some parasites are genetically different from others (chapter 3). These results suggest that the epidemic of schistosomiasis in Northwest Senegal was probably not elicited by a few S. mansoni </>parasites, but that the colonization history is much more complex. It is most likely that a multitude of parasites successfully colonized the local human population. Furthermore, most of the parasite genetic variation observed in the region was found within individual human hosts (chapter 4), suggesting that they accumulate a wide range of parasites during their lifetime. However, children appeared to be much more infected by related parasites than adult hosts, who tended to be infected by more genetically diverse parasites. The age-dependent recruitment of genetically diverse parasite infections may be explained by (1) genotype-dependent concomitant immunity that leads to selective recruitment of genetically unrelated worms with host age, and/or (2) the genetic mixing bowl hypothesis, where older hosts have been exposed to a wider variety of parasites than children.
Currently the cheap and effective drug praziquantel is used to treat schistosomiasis. However, this could lead to serious bottlenecks in S. mansoni</> populations, possibly leading to increased inbreeding, low levels of genetic diversity and the random fixation of (possibly deleterious) alleles. The effect of treatment on the geneticcomposition of S. mansoni</> populations was therefore studied using data obtained from simulations of an island model at equilibrium (chapter 5) and from naturally collected parasites before and after treatment (chapter 6). Both studies showed that treatment has only a limited effect on the genetic diversity of schistosome populations. Complementary simulations revealed that only a sustained treatment policy could decrease schistosome population sizes and therefore drive the success of a control program.
This thesis has shed new light on the factors that shape the distribution of S. mansoni </>parasites. The main conclusion is that S. mansoni </>populations harbor substantial levels of genetic diversity, and hence are able to cope with strong selection pressures such as chemotherapeutic treatment. This large evolutionary potential will hamper attempts either to control or to eliminatethese parasites, as well as complicate the development of new drugs or vaccines.
In this thesis we performed a population genetic study to reveal the distribution of Schistosoma mansoni</> parasites in the basin of the Senegal River (West Africa). Molecular markers such as microsatellites or single nucleotide polymorphisms serve as ideal tools to track the transmission of parasites and infer their ancestry. However, parasite worms cannot be used asa source for DNA as they are inaccessible within the human blood vessels. A protocol was therefore optimized that allowed the sampling, DNA-extraction and molecular analysis based on low quantities of DNA obtained from individual larval parasites (chapter 2). This optimization was an important first step that enabled us to perform multiple analyses on the same individual parasite with low genotyping error rates.
The case study in Northwest Senegal represents one of the most intense epidemic fociof S. mansoni.</> The parasite invaded this area in 1986 after the construction of two dams on the Senegal River. Parasites were obtained at four time points over a period of 14 years (1993-2007) and from several regions (Northwest Senegal, Southeast Senegal and Mali) to study the nature of the S. mansoni</> epidemic (chapter 3). Typing of nuclear and mitochondrial markers revealed that parasites from Northwest Senegal have a West-African origin, that they harbor moderate to high levels of genetic diversity, that they increase in population size and that some parasites are genetically different from others (chapter 3). These results suggest that the epidemic of schistosomiasis in Northwest Senegal was probably not elicited by a few S. mansoni </>parasites, but that the colonization history is much more complex. It is most likely that a multitude of parasites successfully colonized the local human population. Furthermore, most of the parasite genetic variation observed in the region was found within individual human hosts (chapter 4), suggesting that they accumulate a wide range of parasites during their lifetime. However, children appeared to be much more infected by related parasites than adult hosts, who tended to be infected by more genetically diverse parasites. The age-dependent recruitment of genetically diverse parasite infections may be explained by (1) genotype-dependent concomitant immunity that leads to selective recruitment of genetically unrelated worms with host age, and/or (2) the genetic mixing bowl hypothesis, where older hosts have been exposed to a wider variety of parasites than children.
Currently the cheap and effective drug praziquantel is used to treat schistosomiasis. However, this could lead to serious bottlenecks in S. mansoni</> populations, possibly leading to increased inbreeding, low levels of genetic diversity and the random fixation of (possibly deleterious) alleles. The effect of treatment on the geneticcomposition of S. mansoni</> populations was therefore studied using data obtained from simulations of an island model at equilibrium (chapter 5) and from naturally collected parasites before and after treatment (chapter 6). Both studies showed that treatment has only a limited effect on the genetic diversity of schistosome populations. Complementary simulations revealed that only a sustained treatment policy could decrease schistosome population sizes and therefore drive the success of a control program.
This thesis has shed new light on the factors that shape the distribution of S. mansoni </>parasites. The main conclusion is that S. mansoni </>populations harbor substantial levels of genetic diversity, and hence are able to cope with strong selection pressures such as chemotherapeutic treatment. This large evolutionary potential will hamper attempts either to control or to eliminatethese parasites, as well as complicate the development of new drugs or vaccines.
Date:1 Oct 2009 → 20 May 2014
Keywords:Parasitology, Evolution, Schistosomiasis
Disciplines:Microbiology
Project type:PhD project