Fasciola hepatica Kunitz Type Molecule Decreases Dendritic Cell Activation and Their Ability to Induce Inflammatory Responses

Abstract

The complete repertoire of proteins with immunomodulatory activity in Fasciola hepatica (Fh) has not yet been fully described. Here, we demonstrated that Fh total extract (TE) reduced LPS-induced DC maturation, and the DC ability to induce allogeneic responses. After TE fractionating, a fraction lower than 10 kDa (F<10 kDa) was able to maintain the TE properties to modulate the DC pro- and anti-inflammatory cytokine production induced by LPS. In addition, TE or F<10 kDa treatment decreased the ability of immature DC to stimulate the allogeneic responses and induced a novo allogeneic CD4+CD25+Foxp3+ T cells. In contrast, treatment of DC with T/L or F<10 kDa plus LPS (F<10/L) induced a regulatory IL-27 dependent mechanism that diminished the proliferative and Th1 and Th17 allogeneic responses. Finally, we showed that a Kunitz type molecule (Fh-KTM), present in F<10 kDa, was responsible for suppressing pro-inflammatory cytokine production in LPS-activated DC, by printing tolerogenic features on DC that impaired their ability to induce inflammatory responses. These results suggest a modulatory role for this protein, which may be involved in the immune evasion mechanisms of the parasite.

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

“…In contrast, many of them inhibited TLR-induced DC maturation212223242540. However, as reported by Falcon and colleagues26, the inhibitory effect exerted by F. hepatica molecules could be reverted when treatment with LPS was delayed.…”

“…Several studies have independently demonstrated that F. hepatica -derived molecules inhibit or decrease DC activation inducing a tolerogenic phenotype21222324. Furthermore, DCs from mice infected with F. hepatica have a semi-mature phenotype that is characterized by low MHC II and CD40 expression and high secretion of the immunoregulatory cytokine IL-1025.…”

Across intra-mammalian stages of the liver f luke Fasciola hepatica: a proteomic study

“…In addition, it has been demonstrated that proteinase inhibitors may modulate host defenses against ecto- and endoparasites2223.…”

Fasciola and fasciolosis in ruminants in Europe: Identifying research needs

“…One key mechanism that is becoming apparent is that host dendritic cells are targeted by a variety of antigenic fractions, or specific parasite proteins, that modulate the DC phenotype to suppress maturation (Dowling et al., ; Hamilton et al., ) and generate tolerogenic effects (Falcon et al., ) that were subsequently shown to suppress autoimmunity (Carranza et al., ). Specific mediators of these effects have been described including a Knutz‐like molecule (Falcón et al., )and tegumental gylcans (Aldridge & O'Neill, ). Despite this, there is some suggestion that a component of Fasciola can direct a Th1‐like response through DC instruction and this could result in protection (Falcón, Carranza, Aoki, Motrán, & Cervi, ; Noya et al., ).…”

“…including a Knutz-like molecule(Falc on et al, 2014)and tegumental gylcans. Despite this, there is some suggestion that a component of Fasciola can direct a Th1-like response through DC instruction and this could result in protection (Falc on,Carranza, Aoki, Motr an, & Cervi, 2011;Noya et al, 2015).…”