Chemical Biology of Flatworms

Par en May 2017

Schistosomiasis: a major but neglected disease
Among the parasitic diseases, schistosomiasis ranks second only to malaria in terms of its worldwide impact. Nevertheless, it is a “Neglected Tropical Disease” (NTD) as defined in the London Declaration of 2012 which placed the control or elimination of NTDs at the forefront of global efforts to “chart a new course toward health and sustainability among the world’s poorest communities to a stronger, healthier future”. Schistosomiasis, in common with other NTDs, is considered neglected because current investment in control measures and research is incommensurate with its global importance.

Schistosomiasis is caused by parasitic flatworms of the genus Schistosoma. Overall, five species of schistosome infect more than 210 million people with many more at risk, in 78 tropical and sub-tropical countries. The two most widespread species, Schistosoma mansoni, which causes intestinal schistosomiasis, and Schistosoma haematobium, which causes urinary schistosomiasis, are endemic in Africa, S. mansoni also being present in South America and the Caribbean and S. haematobium is present in the Middle East. Two species, Schistosoma japonicum and Schistosoma mekongi are endemic in the Far East, particularly in China, Indochina and the Philippines. However, the fear that a combination of global warming and increased human migration might lead to the disease spreading has been borne out by the recent detection of schistosomiasis transmission in the French Mediterranean island of Corsica. This has been found to be caused by a hybrid between S. haematobium and Schistosoma bovis, a parasite of cattle. The spread of hybrids like this, which is increasingly detected in areas endemic for both species, may have consequences for treatment and control of the disease.

Schistosomiasis is a deadly disease
The severe symptoms of schistosomiasis, which can be a direct cause of death, are due to the deposition of schistosome eggs in the host tissues. Female worms lay hundreds (or thousands in the case of S. japonicum) of eggs daily, most of which pass out of the host via the feces (S. mansoni, S. japonicum) or the urine (S. haematobium), but many become trapped in circulatory capillary systems, particularly in the liver and spleen. Here they induce a local inflammatory reaction, the granuloma, which isolates the egg, but over time their accumulation leads to generalized fibrosis. The resulting portal hypertension, enlarged liver and spleen (hepatosplenomegaly), liver failure with the build-up of ascites and esophageal varices can lead to death in about 10% of patients if not treated. In addition the urogenital form of schistosomiasis, caused by S. haematobium, can also lead to renal failure, is a direct cause of bladder cancer and the lesions it causes in the urogenital tract facilitate HIV infection.

In addition to these severe, overt disease symptoms, schistosomiasis also has more insidious effects, notably anemia and undernutrition, which in turn lead to growth stunting, lower attainment in school, reduced work productivity [1]. All these factors are contributors to the continued poverty of the affected populations.

Schistosomiasis control depends on treatment with a single drug
In the absence of an effective vaccine against schistosomiasis, control of the disease relies solely on treatment with the only available drug, praziquantel. This drug is effective against all species of schistosome, is effective and has few side-effects. It is currently administered in mass treatment, predominately targeting school-age children. However, drawbacks include the size of the pills, which limits administration to young children, who are often heavily infected, and its lack of activity against the larval, migratory stages of the parasite, which contributes to rapid reinfection in high-transmission areas. A major concern is that its current massive application in sub-Saharan Africa will lead to the development of drug resistance by the parasite. Reliance on a single treatment is clearly unsustainable and the development of new chemotherapeutic agents is a priority.
For this reason, our recent research efforts have been directed at characterizing potential drug targets of two types: protein kinases and enzymes involved in epigenetic processes . For the latter, the team has coordinated two successive EC-funded collaborative projects, SEtTReND and A-ParaDDisE, with the aim of developing inhibitors of histone modifying enzymes as novel drugs against schistosomiasis and other NTDs.