Musah-Eroje, Mayowa
(2020)
The Fasciola hepatica growth factor; FhTLM, and actions in immune evasion and parasite survival.
PhD thesis, University of Nottingham.
Abstract
Helminth parasites promote the development of antigen-specific anergy and regulation which often limits pathology but allows parasite survival. Parasite effectors mediating this are the subject of intense study as they may be useful as future vaccine targets. Fasciola hepatica possesses a TGF-like molecule (FhTLM), part of a larger TGF family, which play an important role in regulating parasite development and modulating host immune responses. We hypothesized that F. hepatica may utilise FhTLM to down modulate host immune responses via induction of regulatory. Consequently, in this study, the immuno-modulatory properties of FhTLM with regards to its effect on T-cell mediated immunosuppression and modulation of host immune cells and signals to benefit parasite survival were studied.
The in vitro effect of FhTLM on induction of FoxP3 T-regs cells and anergic markers, PD-1, PD-L1 and CTLA-4, was studied in murine splenic CD4 T-cells. FhTLM failed to upregulate FoxP3 T-reg cells and all investigated anergic T-cell markers. However, production of IL-10, a key immunomodulatory cytokine was significantly enhanced in response to FhTLM stimulation. The interaction of FhTLM with naïve CD4 T-cells also promoted the development of inflammatory responses evidenced by enhanced production of pro-inflammatory cytokines and chemokines (TNF-α, IL-12 P70, IL-1β, IP-10, TARC, MIP-1β, IL-1ra, RANTES and CXCL12). The chemokines induced by FhTLM were biologically functional as supernatants from FhTLM stimulated cells promoted in vitro migration of both activated CD4 T-cells and eosinophils. Lastly, immune signals generated from CD4 T-cells, eosinophils and monocytes failed to support enhanced survival of newly excysted juvenile (NEJs) flukes and this response was not affected by the presence FhTLM. Whilst FhTLM did not directly modulate immune cells to promote parasite survival, induction of pro-inflammatory responses as evidenced by production of cytokines; IL-6, TNF-α, RANTES, MCP-1, Lipocalin -2, Endocan, Pentraxin-3 and ICAM-1 by LPS or IL-4-stimulated monocytes was suppressed or inhibited in the presence of FhTLM.
Taken together, our data highlight an indirect mechanism used by the parasite to benefit parasite persistence and also implicate a role for IL-10 in suppression of protective host immune response to F. hepatica infection. In addition, our data also indicates that FhTLM has an anti-inflammatory potential and may have implications in the treatment of allergic or pro-inflammatory diseases.
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