Investigating the role of Dectin-1 in the host immune responses to Schistosoma mansoni cercariae in acute schistosomiasis 2258025

Abstract

Abstract Introduction Schistosomiasis is a neglected tropical disease caused, in part, by the helminth Schistosoma mansoni, affecting over 250 million people worldwide. While some individuals with chronic infection experience mild symptoms, up to 10% develop severe immunopathology. During advanced infection, parasite eggs are inflammatory and lead to hepatic granulomas, whereas adult worms are immunosuppressive and persist without treatment. Whether cercariae, the only life cycle stage infectious to the mammalian host, are inflammatory or immunosuppressive during cutaneous invasion and early migration is still unknown. More than half of exposed individuals develop Katayama fever, or acute schistosomiasis, characterized by elevated TNF-α and IL-1β in serum, suggesting that acute immune activation contributes to disease severity. Thus, understanding the cercarial life stage may yield novel therapeutic targets that reduce both acute and chronic disease severity. In advanced infection, C-type lectin receptors (CLRs) on myeloid cells recognize egg antigens and induce NLRP3 inflammasome activation. We hypothesize that cercarial components similarly engage CLR Dectin-1 to activate NLRP3 and drive proinflammatory cytokine production. Methods Our lab has developed robust methods for isolating cercarial components and maintaining viable cercariae for in vitro analyses. Results We have found that insoluble cercarial material potently induces IL-1β, TNF-α, and IL-6 secretion from macrophages. Our data also suggests that Dectin-1 signaling through spleen tyrosine kinase (Syk) further exacerbates IL-1β release. Additionally, we found that Dectin-1 is required for caspase-8 cleavage and determined that NLRP3 is the primary inflammasome activated under cercarial stimulation. Conclusion Together, these findings support that cercariae elicit proinflammatory responses from the host during invasion via Dectin-1 mediated NLRP3 inflammasome activation, revealing new insight into the host acute immune response to S. mansoni infection. Funding Source This work was supported by National Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), U.S.A. grant R01 AI148656 to PK and NIH National Institute of General Medical Sciences (NIGMS), U.S.A. grants T32 GM108563-06 and T32 GM154124-01 to MSN. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)