Phenotypic and genotypic monitoring of Schistosoma mansoni in Tanzanian schoolchildren five years into a preventative chemotherapy national control programme

Abstract

Background Schistosoma mansoni is a parasite of profound medical importance. Current control focusses on mass praziquantel (PZQ) treatment of populations in endemic areas, termed Preventative Chemotherapy (PC). Large-scale PC programmes exert prolonged selection pressures on parasites with the potential for, direct and/or indirect, emergence of drug resistance. Molecular methods can help monitor genetic changes of schistosome populations over time and in response to drug treatment, as well as estimate adult worm burdens through parentage analysis. Furthermore, methods such as in vitro drug sensitivity assays help phenotype in vivo parasite genotypic drug efficacy.MethodsWe conducted combined in vitro PZQ efficacy testing with population genetic analyses of S. mansoni collected from children from two schools in 2010, five years after the introduction of a National Control Programme. Children at one school had received four annual PZQ treatments and the other school had received two mass treatments in total. We compared genetic differentiation, indices of genetic diversity, and estimated adult worm burden from parasites collected in 2010 with samples collected in 2005 (before the control programme began) and in 2006 (six months after the first PZQ treatment). Using 2010 larval samples, we also compared the genetic similarity of those with high and low in vitro sensitivity to PZQ.ResultsWe demonstrated that there were individual parasites with reduced PZQ susceptibility in the 2010 collections, as evidenced by our in vitro larval behavioural phenotypic assay. There was no evidence, however, that miracidia showing phenotypically reduced susceptibility clustered together genetically. Molecular analysis also demonstrated a significant reduction of adult worm load over time, despite little evidence of reduction in parasite infection intensity, as measured by egg output. Genetic diversity of infections did not reduce over time, despite changes in the genetic composition of the parasite populations.ConclusionsGenotypic and phenotypic monitoring did not indicate a selective sweep, as may be expected if PZQ treatment was selecting a small number of related “resistant” parasites, but there was evidence of genetic changes at the population level over time. Genetic data were used to estimate adult worm burdens, which unlike parasite infection intensity, showed reductions over time, suggesting the relaxation of negative density-dependent constraints on parasite fecundity with PZQ treatment. We thereby demonstrated that density-dependence in schistosome populations may complicate evaluation and monitoring of control programmes.Electronic supplementary materialThe online version of this article (10.1186/s13071-017-2533-6) contains supplementary material, which is available to authorized users.

Parasite Population Genetic Contributions to the Schistosomiasis Consortium for Operational Research and Evaluation within Sub-Saharan Africa

“…Although this could potentially reflect species differences between S. haematobium and S. mansoni , consistent with their contrasting mean daily egg output per adult worm, it is important to acknowledge that the aforementioned Tanzanian S. mansoni populations represented a true pretreatment baseline population, 44 whereas these Zanzibar S. haematobium populations had been subjected to many previous treatments, over several years, with PZQ before the start of the SCORE/ZEST program. 62 Indeed, within these Zanzibarian S. haematobium populations, there was evidence of density dependence within individuals in relation to host age and gender (and, hence, also infection intensity profiles), consistent with that previously documented through population genetic analyses for both S. mansoni in Tanzania 31 , 47 and S. haematobium in Mali. 44 Furthermore, population genetic and statistical analyses did indicate inherent differences in schistosome fecundity levels by site across both islands, frequently consistent with those shehias that went on to be classed as nonresponder hotspot sites.…”

“…One recent population genetic study, however, estimated the number of adult worm genotypes of S. mansoni in Tanzanian children using parentage analysis and sibship reconstruction from microsatellite analyses of miracidia. 47 Analyses using our newly developed statistical tools indicated that, despite the (minimum) number of adult worm pairs present in school-aged children having reduced over time in response to PZQ treatment, there was little or no evidence of any corresponding reduction in parasite infection intensities, as measured by EPG. This indicated there was a relaxation of the density-dependent inhibition on schistosome fecundity following treatment with PZQ among these S. mansoni populations.…”

“…This is consistent with the previous work that observed that most of the genetic diversity in S. mansoni occurs at the human host level, rather than at the village or district level. 44 , 46 , 47 Infrapopulation genetic diversity is usually interpreted as the combined outcome of the genetic diversity of parasites circulating in the environment, differences in exposure due to variability in host behaviors, particularly those related to water contact; that is, location, duration, and time of day, as well as parasite establishment, often dependent on host gender and immune response. These factors could well be predicted to dilute any effect imposed by the SCORE-contrasting treatment arms, particularly under conditions of the high gene flow that was apparent across these lacustrine Tanzanian populations.…”

Elucidation of Cellular Responses in Non-human Primates With Chronic Schistosomiasis Followed by Praziquantel Treatment

“…Praziquantel (PZQ), a drug co-developed by Bayer AG and Merck KGaA in the 1970s, has been implemented in many national programs as an integral component of control and elimination strategies and is the drug of choice for the treatment of schistosomiasis (Olveda et al, 2016;Bergquist et al, 2017;Gower et al, 2017;Kabore et al, 2017;Kimani et al, 2018). Although PZQ is considered non-toxic and highly effective against adult schistosomes, it is unable to kill developing schistosomes and the individual remains susceptible to subsequent infections.…”

Opportunities and challenges for modelling epidemiological and evolutionary dynamics in a multihost, multiparasite system: Zoonotic hybrid schistosomiasis in West Africa

“…Furthermore, different pairings may result in different fecundity rates. This poses significant challenges, but molecular approaches such as parentage and/or sib‐ship analysis of schistosome eggs present opportunities to improve assumptions regarding association between egg output and number of worm pairs in an individual (Lu et al., ; Gower, Gehre, Marques, Lwambo, & Webster, ).…”