In VitroAntihydatic Action of IFN-γIs Dependent on the Nitric Oxide Pathway

Abstract

Hydatidosis is a widely endemic helminthic disease vectored in human by the larval stage of the metacestode Echinococcus granulosus. It is characterized by the long-term coexistence of chronic infection with detectable humoral and cellular responses against the macroparasite. Previous studies demonstrated interferon-gamma (IFN-gamma) and nitric oxide (NO) production (in vivo and in vitro) during hydatidosis. In this study, we tested the hypothesis that NO production after IFN-gamma induction may constitute a host defense against E. granulosus. We also investigated the IFN-gamma effect on protoscolices (larval form of the parasite) viability in coculture with hydatid patients' peripheral blood mononuclear cells (PBMC). PBMCs from hydatic patients incubated with IFN-gamma (100 U/mL) alone are effective in the killing of protoscolices. This scolicidal activity is concomitant with elevation of nitrite levels. NO release and cytotoxic activity are inhibited by N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the NO pathway and increased by L-arginine, an NO precursor, and tetrahydrobiopterin (BH4), a nitric oxide synthase (NOS) cofactor. Our results indicate that IFN-gamma mediated iNOS induction as one of host defense mechanism against human E. granulosus infection.

Involvement of nitric oxide and its up/down stream molecules in the immunity against parasitic infections

“…Controversially, some researchers reported NO-mediated immunosuppression following murine Echinococcus infection [131] and the high level of NO production during chronic infection, which contribute more to immunosuppression than to limitation of parasite growth [132]. Results indicated that IFN-ã mediated iNOS is induced as one of host defense mechanism against human E. granulosus infection [133]. Collectively, the data indicated that NO concentration correlate with IFN-γ levels, and overall suggest that their production together play a role in the host defense mechanisms in human hydatidosis [134].…”

A protective effect of the laminated layer on Echinococcus granulosus survival dependent on upregulation of host arginase

“…Our team has previously recognized interferon-gamma (IFN-γ) as the major mediator of host resistance against this parasite (Amri et al, 2007;Touil-Boukoffa et al, 1997. Production of reactive nitrogen intermediates including nitric oxide (NO) is thought to represent an important scolicidal mechanism of IFN-γ-activated human monocytes.…”

“…Production of reactive nitrogen intermediates including nitric oxide (NO) is thought to represent an important scolicidal mechanism of IFN-γ-activated human monocytes. In fact, the inhibition of NOS2 (inducible NO synthase) activity and expression by NOS inhibitor (L-NMMA) (Amri et al, 2007) and cytokines (IL-10 and IL-4) (Amri et al, 2009) led to decrease the parasite killing.…”

Echinococcosis

“…Effector mechanisms include neutrophils and macrophage activation, nitric oxide (NO), eosinophil cationic protein, complement, and antibodies (Virginio et al 2007;Amri et al 2007;Ferreira et al 2000a;Heath et al 1994;Jenkins et al 1990;Ramos et al 2006;Ferragut and Nieto 1996;Severi et al 1997;Zhang et al 2003b;Riley et al 1986;Dempster et al 1992). Around live intact cysts there is a remarkably scarce inflammatory reaction, as opposed to regressive cysts (Breijo et al 2008;Coltorti and Varela-Diaz 1974;Marco et al 2006;Sakamoto and Cabrera 2003).…”

“…Increased Th1 responses (IFNγ or IL-12) impair PSC survival and cyst development, while IL-4 and IL-10 induce heavier cyst loads and impair PSC killing (Al-Qaoud and Abdel-Hafez 2008; Amri et al 2007Amri et al , 2009). Other mechanisms of immune evasion include polyclonal activation of B cells (Cox et al 1989) and induction of IL-10, IgG4, and high levels of nonspecific antibodies and lack of antibody avidity maturation, as shown experimentally by injection of carbohydrate fractions of PSC (Miguez et al 1996;Mourglia-Ettlin et al 2011a;Ferragut and Nieto 1996;Severi et al 1997;Baz et al 1999Baz et al , 2008Cardozo et al 2002;Dematteis et al 2001).…”