iNOS is essential to maintain a protective Th1/Th2 response and the production of cytokines/chemokines against Schistosoma japonicum infection in rats.

Humans and a wide range of mammals are generally susceptible to Schistosoma infection, while some rodents such as Rattus rats and Microtus spp are not. We previously demonstrated that inherent high expression levels of nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), plays an important role in blocking the growth and development of Schistosoma japonicum in wild-type rats. However, the potential regulatory effects of NO on the immune system and immune response to S. japonicum infection in rats are still unknown. In this study, we used iNOS-knockout (KO) rats to determine the role of iNOS-derived NO in the immune system and immunopathological responses to S. japonicum infection in rats. Our data showed that iNOS deficiency led to weakened immune activity against S. japonicum infection. This was characterized by the impaired T cell responses and a significant decrease in S. japonicum-elicited Th2/Th1 responses and cytokine and chemokine-producing capability in the infected iNOS-KO rats. Unlike iNOS-KO mice, Th1-associated cytokines were also decreased in the absence of iNOS in rats. In addition, a profile of pro-inflammatory and pro-fibrogenic cytokines was detected in serum associated with iNOS deficiency. The alterations in immune responses and cytokine patterns were correlated with a slower clearance of parasites, exacerbated granuloma formation, and fibrosis following S. japonicum infection in iNOS-KO rats. Furthermore, we have provided direct evidence that high levels of NO in rats can promote the development of pulmonary fibrosis induced by egg antigens of S. japonicum, but not inflammation, which was negatively correlated with the expression of TGF-β3. These studies are the first description of the immunological and pathological profiles in iNOS-KO rats infected with S. japonicum and demonstrate key differences between the responses found in mice. Our results significantly enhance our understanding of the immunoregulatory effects of NO on defensive and immunopathological responses in rats and the broader nature of resistance to pathogens such as S. japonicum. Author summary: Schistosomiasis is a zoonosis that affects more than 200 million people worldwide. A wide range of mammals, including mice, are permissive hosts of Schistosoma and develop chronic disease characterized by egg-granuloma formation and fibrosis after infection. Rats, on the other hand, are non-permissive hosts and develop efficient immune responses to eliminate the worms. Interestingly, schistosome eggs elicit a dominant Th2 immune response within mouse hosts, whereas rats with schistosomiasis develop a significant Th2 response in the absence of available egg production. The Th2 response in rats seems to play an essential role in the protection of the host against Schistosoma. So far, the factors that lead to the different immune responses to Schistosoma infection in both hosts have not been demonstrated. In this study, our results show that an iNOS-dependent mechanism maintains the function of the immune system in rats by modulating CD4+ T cell-mediated Th1/Th2-associated cytokine responses and chemokine production. Additionally, the absence of iNOS led to slow clearance of parasites, increases in the development of worms, and an exacerbation of granuloma formation and fibrosis in rats. Furthermore, high levels of NO in rats can promote the development of fibrosis induced by inflammation (rapid inflammatory repair). Therefore, this study demonstrates that the difference in iNOS levels between mice and rats is responsible for the different immune responses and outcomes induced by schistosome infection in both hosts. [ABSTRACT FROM AUTHOR]