Two-year longitudinal survey reveals high genetic diversity of Schistosoma mansoni with adult worms surviving praziquantel treatment at the start of mass drug administration in Uganda

Abstract

BackgroundA key component of schistosomiasis control is mass drug administration with praziquantel. While control interventions have been successful in several endemic regions, mass drug administration has been less effective in others. Here we focus on the impact of repeated praziquantel treatment on the population structure and genetic diversity of Schistosoma mansoni.MethodsWe examined S. mansoni epidemiology, population genetics, and variation in praziquantel susceptibility in parasites isolated from children across three primary schools in a high endemicity region at the onset of the Ugandan National Control Programme. Children were sampled at 11 timepoints over two years, including one week and four weeks post-praziquantel treatment to evaluate short-term impacts on clearance and evidence of natural variation in susceptibility to praziquantel.ResultsPrevalence of S. mansoni was 85% at baseline. A total of 3576 miracidia larval parasites, isolated from 203 individual children, were genotyped at seven loci. Overall, genetic diversity was high and there was low genetic differentiation, indicating high rates of parasite gene flow. Schistosome siblings were found both pre-treatment and four weeks post-treatment, demonstrating adult worms surviving treatment and natural praziquantel susceptibility variation in these populations at the beginning of mass drug administration. However, we did not find evidence for selection on these parasites. While genetic diversity decreased in the short-term (four weeks post-treatment), diversity did not decrease over the entire period despite four rounds of mass treatment. Furthermore, within-host genetic diversity was affected by host age, host sex, infection intensity and recent praziquantel treatment.ConclusionsOur findings suggest that praziquantel treatments have short-term impacts on these parasite populations but impacts were transient and no long-term reduction in genetic diversity was observed. High gene flow reduces the likelihood of local adaptation, so even though parasites surviving treatment were observed, these were likely to be diluted at the beginning of the Ugandan National Control Programme. Together, these results suggest that MDA in isolation may be insufficient to reduce schistosome populations in regions with high genetic diversity and gene flow.

A Darwinian outlook on schistosomiasis elimination

“…These results are consistent with observations of sustained levels of genetic diversity during field-based genetic studies, which targeted school-age children (presumably achieving a coverage lower than 95%) in medium/high endemicity regions (Table 1). Similar to our observations, Gower and colleagues found a significant reduction in adult worm load [37] and Faust and colleagues found a decrease in genetic diversity shortly after treatment [38], while both studies found no decrease in diversity over the entire period of the study. Altogether, these results clearly suggest that treatment has only shortterm impacts -important to reduce the adult worm load of the patient -but not sufficient to affect long-term parasite population dynamics.…”

“…This is a direct consequence of the population being panmictic: almost all genetic variability present within the component population will be found within each individual infrapopulation. Genetic studies assessing the impact of treatment in natural populations found no significant differences in genetic diversity between hosts and/or villages [32,[34][35][36][37][38], a pattern typically observed for Schistosoma that supports a panmictic parasite population [45,62]. Hence, untreated individuals will not only act as continued reservoirs of transmission [63][64][65], but also act as reservoirs of regional genetic diversity.…”

“…The mortality bPZQ was not set to 100% because there are many factors that lower PZQ effectiveness, such as i) PZQ is not effective against immature worms present within the host, ii) PZQ is less effective in lightly infected patients that show less robust immune responses [53], and iii) there is variability in PZQ susceptibility among schistosome strains (at least in S. mansoni) [54]. Indeed, parentage analyses based on microsatellite and genomic data suggested that adult worms survive treatment [38,55]. The coverage of treatment (i.e.…”

“…However, full coverage is rarely achieved in natural conditions because of parasite refugia, namely the group of parasites that are not reached during a control program [30]. Beside the untreated host individuals (see above), there are other possible refugia such as are larval stages within infested water or intermediate snail hosts, immature worms that escape treatment within human hosts [67], adult worms that survive treatment [38] and alternative reservoir host species such as rodents or baboons that are not reached during MDA [68,69]. In addition, studies have shown a substantial decline of compliance over prolonged chemotherapy campaigns (leaving hosts uncured) [70][71][72], and of praziquantel efficacy in schools with higher exposure to MDA (leaving worms surviving treatment) [73].…”

“…At least in experimental infections, it has been proven that PZQ treatment decreases S. mansoni genetic diversity and increases endogamy [33]. Over the past decade, a total of seven studies quantified the genetic diversity of natural S. mansoni populations in sub-Saharan Africa in response to MDA treatment using microsatellites (repeat sequences in DNA that are used to fingerprint individual parasites) [32,[34][35][36][37][38] or partial mitochondrial gene sequences [39]. Most of the genetic studies occurred in regions of high endemicity (≧50% infection prevalence among school age children as determined by parasitological methods) ( Table 1).…”