Abstract
Infection of the mammalian host by the parasitic helminth Schistosoma mansoni is accompanied by the release of excretory/secretory molecules (ES) from cercariae which aid penetration of the skin. These ES molecules are potent stimulants of innate immune cells leading to activation of acquired immunity. At present however, it is not known which cells take up parasite antigen, nor its intracellular fate. Here, we develop a technique to label live infectious cercariae which permits the imaging of released antigens into macrophages (MΦ) and dendritic cells (DCs) both in vitro and in vivo. The amine reactive tracer CFDA-SE was used to efficiently label the acetabular gland contents of cercariae which are released upon skin penetration. These ES products, termed ‘0-3hRP’, were phagocytosed by MHC-II+ cells in a Ca+ and actin-dependent manner. Imaging of a labelled cercaria as it penetrates the host skin over 2 hours reveals the progressive release of ES material. Recovery of cells from the skin shows that CFDA-SE labelled ES was initially (3 hrs) taken up by Gr1+MHC-II− neutrophils, followed (24 hrs) by skin-derived F4/80+MHC-IIlo MΦ and CD11c+ MHC-IIhi DC. Subsequently (48 hrs), MΦ and DC positive for CFDA-SE were detected in the skin-draining lymph nodes reflecting the time taken for antigen-laden cells to reach sites of immune priming. Comparison of in vitro-derived MΦ and DC revealed that MΦ were slower to process 0-3hRP, released higher quantities of IL-10, and expressed a greater quantity of arginase-1 transcript. Combined, our observations on differential uptake of cercarial ES by MΦ and DC suggest the development of a dynamic but ultimately balanced response that can be potentially pushed towards immune priming (via DC) or immune regulation (via MΦ).
Highlights
Trematode parasites (e.g. Schistosoma sp, Fasicola sp, and Trichobilharzia sp) are important parasites of mammalian hosts in the developing, as well as the developed world, and cumulatively are a major health burden to humans and domestic animals
Phagocytic macrophages and dendritic cells in the skin internalised excretory/secretory molecules released by the larvae, and both cell types were subsequently located in the draining lymph nodes where priming of the acquired immune response occurs
In vitro studies determined that macrophages were slower to process released parasite material than dendritic cells; they secreted lower levels of pro-inflammatory cytokines but greater quantities of regulatory IL-10
Summary
Trematode parasites (e.g. Schistosoma sp, Fasicola sp, and Trichobilharzia sp) are important parasites of mammalian hosts in the developing, as well as the developed world, and cumulatively are a major health burden to humans and domestic animals. Infective schistosome larvae gain entry to the host as freeswimming cercariae which penetrate the host via a percutaneous route. The precise mechanism by which Schistosoma larvae penetrate the skin to facilitate their onward migration is a matter of debate [1,2,3]. Excretory/secretory (ES) molecules released by invading larvae aid penetration of the skin and lead to the stimulation, and down-regulation, of the dermal inflammatory response [6]. The extended contact between ES molecules released by invading larvae and innate immune cells in the skin, following exposure to protective radiation-attenuated (RA) larvae [7], indicates that the innate response may be critical in limiting the success of initial infection. The innate immune system in the skin could provide a target for manipulation in the pursuit of anti-schistosome vaccines and/or drugs but the cellular target(s) and mechanisms by which larval
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