Authors

E Driciru³; JP Koopman¹; RA Steenbergen¹; F Sonnet¹; KA Stam¹; JJ Janse¹; HM Bes-Roeleveld¹; E Iliopoulou¹; I Nambuya²; JC Sijtsma¹; YC Kruize¹; A van Diepen¹; C Hokke¹; M Egesa³; AS MacDonald²; H Mpairwe³; M Yazdanbakhsh¹; A Elliott³; M Roestenberg¹; EL Houlder¹;  ¹ Leiden University Medical Centre, Netherlands;  ² University of Manchester, UK;  ³ MRC/UVRI and LSHTM Uganda Research Unit, Uganda

Discussion

Prior studies have revealed mixed Type-1/Type 2 response in early migrating and maturing Schistosoma mansoni (Sm) infection, developing to a Type-2 and regulatory response upon egg production. These findings have been mainly derived from animal (murine) models, as longitudinal assessment of how worm-specific immune responses develop in humans has not been possible. Here, we have used a Sm controlled human infection model (Sm-CHI) to study immune response development over repeat (3x) male-cercariae exposure (Netherlands, n=24), comparing our findings to natural infection (Uganda, n=30). Sm-specific cellular and cytokine responses were assessed via spectral flow cytometry and luminex. Clinically, repeated Sm-CHI led to reduced symptoms (when compared to single), but did not result in (sterile) protection. In line with this symptom profile, Type-1 responses (serum CXCL10, activated CD38⁺HLADR⁺ T cells) peaked post exposure one and two, reducing post exposure three. In contrast, Sm-specific regulatory and Th2 responses increased with repeat exposure. Five Sm-CHI participants were inadvertently exposed to female (instead of male) cercariae during exposure two. This led to a potential mixed-sex infection and one positive Sm faecal PCR post exposure three before praziquantel treatment, indicative of low-level egg production. An elevated Type-2 response was observed in mixed-sex exposed individuals, with eosinophilia and Sm-specific Th2 cytokine production. Sm-specific Th2 responses in mixed-sex Sm-CHI were significantly higher than those observed in endemic natural infection, likely attributable to well-described immunoregulation induced by chronic Sm infection. Taken together, this data significantly advances our understanding of human immune response development during schistosome infection.