Mechanisms of Praziquantel Resistance in Schistosoma haematobium: Evidence from Nigerian Clinical Isolates and Experimental Models

The emergence of reduced praziquantel susceptibility in Schistosoma haematobium populations following repeated mass drug administration cycles represents a growing concern for schistosomiasis elimination programmes in West Africa, yet the underlying resistance mechanisms remain poorly characterised. This doctoral study investigated molecular and phenotypic mechanisms of praziquantel tolerance in S. haematobium clinical isolates from high-coverage mass drug administration communities in Kano and Sokoto states, Northwest Nigeria. Adult worms recovered from experimentally infected hamsters challenged with miracidia from field-collected eggs were subjected to in vitro drug susceptibility assays. Transcriptomic profiling of drug-tolerant versus susceptible worms was performed by RNA sequencing. Target site candidate genes including voltage-gated calcium channel subunit SmCav1A homologue, multidrug resistance-associated protein genes, and ABC transporter genes were analysed by quantitative PCR and sequencing. In vitro effective concentration 50 values were significantly higher in worms from communities with eight or more prior treatment rounds compared to communities with fewer than four rounds (p = 0.003). RNA sequencing identified upregulation of ABC transporter genes and downregulation of calcium channel expression in tolerant worms. These findings constitute the first molecular evidence of selection for praziquantel tolerance in Nigerian S. haematobium populations and provide a mechanistic framework to guide development of resistance monitoring protocols. Keywords: praziquantel resistance, Schistosoma haematobium, drug tolerance mechanisms, ABC transporters, Nigeria.