A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity

Abstract

Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1-polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN-γ secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-γ secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, Fhmuc-treated DC conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies.

Characterization of dendritic cells and follicular dendritic cells in the hepatic lymph nodes and liver of sheep experimentally infected with Fasciola hepatica

“…It has been reported that in fixed sheep lymph nodes, MHC-II is expressed at high levels by interdigitating cells present in the paracortex, at lower levels by the B lymphocytes present in the follicles, and at a lower level in macrophages from the medullary sinuses [13], an expression pattern also observed in our study. In the present study, the reduced MHC-II+ DC found in HLNs at 9 and 18 dpi, compared to the number in the UC group, agrees with the significant decrease in MHC-II in the peritoneal leukocytes of sheep experimentally infected with F. hepatica at 9 dpi [54], with the reduced expression of MHC-II in DC from buffalos cultured in the presence of ESPs from F. gigantica [20], and with the low MHC-II expression in DC of mice cultured in the presence of mucin-like peptide [30,65] or in the presence of FhTeg from F. hepatica [18].…”

“…On the other hand, it has been shown that recombinant forms of FhCL1 and FhGST can partially activate DC [10]. Moreover, a mucin-like peptide from F. hepatica (Fhmuc) induces parasite-specific adaptive immunity with increased levels of IFN-γ and specific IgG antibodies [30]. In a recent study, it was also reported that the interactions of DC with F. hepatica cathepsin L3 (FhCL3) confer a unique expression pattern of the cytokines IFN-γ and IL-13, which may be protective in this parasitosis or in other helminth infections [31].…”

Fasciola hepatica-Derived Molecules as Regulators of the Host Immune Response

“…In contrast to other F. hepatica ES products discussed here, but similar to FhCL1 and FhGST-si ( 41 ), Fhmuc elicits pro-inflammatory properties, with increased LPS-induced TLR4 expression in DCs and polarization of the T cell response ( 59 ). This ability of F. hepatica to modulate the host immune response may have potential implications for vaccination strategies ( 59 ). As F. hepatica ES products contain significant levels of glycans, it is probable that native F. hepatica mucin-like peptides undergo glycosylation, which is not represented with the synthetic peptide.…”

“…Analysis of the NEJ stage of F. hepatica infection led to the discovery of proteins with similarities to mucins ( 57 , 58 ). A synthetic mucin-derived peptide (Fhmuc) increased peritoneal CD11b + MHCII + cells in mice exposed to LPS ( 59 ). In contrast to other F. hepatica ES products discussed here, but similar to FhCL1 and FhGST-si ( 41 ), Fhmuc elicits pro-inflammatory properties, with increased LPS-induced TLR4 expression in DCs and polarization of the T cell response ( 59 ).…”

“…A synthetic mucin-derived peptide (Fhmuc) increased peritoneal CD11b + MHCII + cells in mice exposed to LPS ( 59 ). In contrast to other F. hepatica ES products discussed here, but similar to FhCL1 and FhGST-si ( 41 ), Fhmuc elicits pro-inflammatory properties, with increased LPS-induced TLR4 expression in DCs and polarization of the T cell response ( 59 ). This ability of F. hepatica to modulate the host immune response may have potential implications for vaccination strategies ( 59 ).…”