IL-10 Blocks the Development of Resistance to Re-Infection with Schistosoma mansoni

Abstract

Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4 ⁺CD44 ⁺CD25 ⁺GITR ⁺ lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni.

Author Summary

Schistosomes are zoonotic parasitic helminths that infect hundreds of millions of people worldwide. Despite effective chemotherapy, schistosomiasis- the disease caused by these parasites, still plagues tropical regions of the world. This is due, in part, to poor resistance to reinfection resulting in high re-infection rates following treatment. This lack of resistance is intriguing, as effective treatment relies upon drug-induced parasite damage combined with host immune mediated killing. Furthermore, it has been widely reported that post-treatment, individuals develop and retain elevated levels of anti-parasite immune responses. We therefore asked why resistance to re-infection is so poor, despite the development of significant anti-worm responses post-treatment.

It is essential that immune responses are controlled by various immunosuppressive mechanisms to prevent immune-mediated pathologies. However, a robust immunoregulatory response may obstruct the development of protective immunity. Thus, a balanced immune response providing a non-pathogenic yet effective immune response may be required for the development of effective resistance to reinfection. Understanding the immunological mechanisms of resistance to re-infection and the role of effector and regulatory responses may aid in the development of more effective vaccines and treatment strategies for schistosomaisis. This study suggests that combining chemotherapy with drugs that block IL-10 might provide an improved strategy to elicit acquired immunity to this parasite.