EFFECT OF PRAZIQUANTEL TREATMENT ON HEPATIC EGG GRANULOMAS IN MICE INFECTED WITH PRAZIQUANTEL-SUSCEPTIBLE AND -RESISTANT SCHISTOSOMA JAPONICUM ISOLATES

Currently, praziquantel is the drug of choice for treatment of human Schistosoma japonicum infections in China. Although no evidence of resistance to praziquantel has been detected following repeated and extensive chemotherapy with praziquantel for more than 30 years in endemic foci of the country, there were several patients with S. japonicum infection who failed in standard praziquantel treatment, and praziquantel-resistant isolates of S. japonicum have been successfully generated in a mouse model. This study assessed the effect of praziquantel treatment on pathological damages to mice infected with praziquantel-susceptible and -resistant S. japonicum isolates. Mice were each infected percutaneously with 20 cercariae of praziquantel-resistant and -susceptible S. japonicum isolates, and then randomly grouped. Mice in the treatment groups were administered a single dose (150 kg/mg) of praziquantel at day 35 post-infection, while infected but untreated mice served as controls. Mice were sacrificed on day 42 or 49 postinfection, the area and circumference of the hepatic egg granulomas in fresh liver specimens were measured. In infected but untreated mice, there were no significant differences in the area and circumference of the hepatic egg granulomas between praziquantel-resistant and -susceptible isolates, whereas in praziquantel-treated mice, the area or circumference of hepatic egg granulomas were significantly greater in mice infected with the praziquantel-resistant than in those harboring Praziquantel on S. japonicum-induced liver Granulomas Vol 49 No. 2 March 2018 209 INTRODUCTION Schistosomiasis, caused by infection with blood flukes of the genus Schistosoma, remains a global public health concern (Colley et al, 2014). This neglected tropical disease is reported to be endemic in 78 countries and more than 200 million people are estimated to have the disease across the world, with a further 800 million at risk of infection (Qu et al, 2016). Currently, mass drug administration (MDA) with praziquantel is implemented as the major global strategy for schistosomiasis control (Ross et al, 2015). However, there is a growing concern on the emergence of praziquantel-resistant parasites (Wang et al, 2012b), following long-term and extensive use of the agent since its introduction in late 1970s (Gönnert and Andrews, 1977). In Africa, there are increasing evidences demonstrating praziquantel-resistant S. mansoni has already exists in endemic foci (Doenhoff et al, 2002; Melman et al, 2009; Bergquist et al, 2017; Vale et al, 2017). Since the 1980s, praziquantel has replaced other schistosomicides to become the drug of choice for the treatment of human S. japonicum infections in China (Chen, 2005; Xiao et al, 2010). Following repeated and extensive chemotherapy with praziquantel for more than 30 years in ten endemic foci of the country, there is still no evidence of resistance to praziquantel; however, there are several patients with S. japonicum infection who fail in standard praziquantel treatment at a single oral dose of 40 mg/kg or at a single dose of 30 mg/kg administered for two successive days (Liang et al, 2001a; Wang et al, 2010, 2012a; Seto et al, 2011). In addition, praziquantel resistance was experimentally induced in S. japonicum in a mouse model, demonstrating that the parasites are capable of developing resistance to praziquantel when sufficiently given under drug pressure (Liang et al, 2011). Previous studies detected higher in vitro response to praziquantel at the egg, miracidial, cercarial and adult stages of praziquantel-susceptible S. mansoni isolates than drug-resistant isolates (Liang et al, 2001b). In addition, mice infected with praziquantel-resistant S. mansoni isolates shed more eggs in their feces than mice carrying drug-susceptible parasites, and the praziquantel-resistant isolates appear more pathogenic in mice than susceptible parasites (Liang et al, 2001c). Similarly, there is a clear cut reduction in the responses to praziquantel at the miracidial, cercarial and adult stages of praziquantel-resistant S. japonicum isolates than praziquantel-susceptible parasites (Li et al, 2011). However, the pathological damages of praziquantelresistant S. japonicum to mammalian hosts remain unknown. Hence, the present study was designed to assess the effect of praziquantel treatment on hepatic egg granulomas in mice infected with praziquantel-susceptible and -resistant S. japonicum isolates and, thereby, obtain information of the praziquantel-susceptible isolates (p<0.01). These results demonstrate praziquantel treatment causes more reductions in the size of hepatic egg granulomas in mice infected with praziquantel-susceptible S. japonicum isolates than in those infected with drug-resistant parasites, indicating eggs from praziquantel-susceptible isolates are more sensitive to praziquantel than those from the drug resistant isolates.