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Nitric oxide blocks the development of the human parasite Schistosoma japonicum

Significance Viable egg production by Schistosoma species is the key pathogenic process causing granuloma formation in permissive hosts (e.g., mice), while nonpermissive hosts [e.g., Norway rats (Rattus norvegicus)] avoid such sequelae. Using inducible nitric oxide synthase knockout (iNOS−/−) rats, we demonstrate that high expression levels of iNOS in rats play an important role in blocking the egg-induced granuloma formation of Schistosoma japonicum. The nitric oxide, produced by iNOS, inhibits parasite growth, reproductive organ development, egg production, and viability by interfering with mitochondrial function. This study solves the puzzle as to why rats are naturally resistant to S. japonicum infection and provides insights for understanding the pathogenesis of human schistosomiasis and the interactions between host and parasite. Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS−/−) Sprague–Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS−/− rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host–parasite interactions and drug development strategies against schistosomiasis.