Early Induction of Human Regulatory Dermal Antigen Presenting Cells by Skin-Penetrating Schistosoma Mansoni Cercariae

Abstract

Following initial invasion of Schistosoma mansoni cercariae, schistosomula reside in the skin for several days during which they can interact with the dermal immune system. While murine experiments have indicated that exposure to radiation-attenuated (RA) cercariae can generate protective immunity which is initiated in the skin stage, contrasting non-attenuated cercariae, such data is missing for the human model. Since murine skin does not form a reliable marker for immune responses in human skin, we used human skin explants to study the interaction with non-attenuated and RA cercariae with dermal innate antigen presenting cells (APCs) and the subsequent immunological responses. We exposed human skin explants to cercariae and visualized their invasion in real time (initial 30 min) using novel imaging technologies. Subsequently, we studied dermal immune responses and found an enhanced production of regulatory cytokine interleukin (IL)-10, pro-inflammatory cytokine IL-6 and macrophage inflammatory protein (MIP)-1α within 3 days of exposure. Analysis of dermal dendritic cells (DDCs) for their phenotype revealed an increased expression of immune modulators programmed death ligand (PD-L) 1 and 2, and increased IL-10 production. Ex vivo primed DDCs suppress Th1 polarization of naïve T-cells and increase T-cell IL-10 production, indicating their regulatory potential. These immune responses were absent or decreased after exposure to RA parasites. Using transwells, we show that direct contact between APCs and cercariae is required to induce their regulatory phenotype. To the best of our knowledge this is the first study that attempts to provide insight in the human dermal S. mansoni cercariae invasion and subsequent immune responses comparing non-attenuated with RA parasites. We reveal that cercariae induce a predominantly regulatory immune response whereas RA cercariae fail to achieve this. This initial understanding of the dermal immune suppressive capacity of S. mansoni cercariae in humans provides a first step toward the development of an effective schistosome vaccine.

The peripheral immune response of mice infected with a neuropathogenic schistosome

“…The production of IL‐10 seems to be restricted to the infected skin since no changes in IL‐10 levels were noticed in serum samples and also Il10 expression in the spleen remained unchanged. This is in accordance with the data from S. mansoni ‐infected skin, where direct contact with cercariae was necessary to induce regulatory phenotype of monocyte‐derived dendritic cells 31 . However, deeper exploration of cellular source of IL‐10 is warranted.…”

“…As for Tregs, it is in contrast with their unchanged presence in the periphery DLN or spleen in early Schistosoma mansoni infection 28‐30 . Here, IL‐10 is produced by CD4+ T cells, 30 specifically Th2 28 or dermal dendritic cells 31 . The regulatory milieu might be induced, among others, by skin commensal bacteria 30 .…”

A library of cell-surface and secreted proteins fromSchistosoma mansoniidentifies early serological markers of infection

“…Quantitation of gene expression suggests that these genes are, however, already actively transcribed at the schistosomula stage [15,54,55], several weeks before reactivity from host antibodies can be detected. The ability of schistosomes to manipulate and evade the host immune system has been described although the specific proteins and mechanisms orchestrating this escape are not yet clearly defined [57][58][59][60].…”

Monocyte and Macrophage-Mediated Pathology and Protective Immunity During Schistosomiasis

“…Penetration of cercariae into host's skin induces the influx of neutrophils (Paveley et al, 2009), as well as the activation of resident macrophages, Langerhans cells (Kumkate et al, 2007) and dendritic cells (DCs) (Winkel et al, 2018). Upon activation by S. mansoni cercariae, resident macrophages release IL-10, while DCs produce IL-6, IL-12p40, TNF-α to activate the adaptive immune response in skin-draining lymph nodes (sdLN) (Mountford and Trottein, 2004;Paveley et al, 2009).…”

“…Upon activation by S. mansoni cercariae, resident macrophages release IL-10, while DCs produce IL-6, IL-12p40, TNF-α to activate the adaptive immune response in skin-draining lymph nodes (sdLN) (Mountford and Trottein, 2004;Paveley et al, 2009). For that, DCs increase the expression of HLA-DR, CD80, CD86, PDL-1, and PD-L2, interact with T cells and coordinate Th2 polarization (Winkel et al, 2018). Moreover, cercariae antigens are internalized by macrophages and influence CD4 + IL-4 + T cells responses in sdLN (Paveley et al, 2011).…”