Differential regulation of murineMesocestoides cortiinfection by bacterial lipopolysaccharide and interferon-γ

Abstract

Many liver-invasive parasites cause extensive liver damage which may result in an impaired ability to catabolize endotoxin. The influence of endogenous endotoxin on the progress of liver-invasive parasitic diseases has been investigated in murine Mesocestoides corti infection. Invasion of liver tissue by tetrathyridia resulted in extensive parenchymal destruction with fibrosis. In association with this, undetoxified endotoxin, in potentially biologically active concentration, was found on peritoneal macrophages, 5 months post-M, corti infection. Host susceptibility was influenced by the Lps gene for responsiveness to lipopolysaccharide (LPS). The parasite burden of LPS-responsive (C3H/HeN) mice was significantly increased in the livers of these mice when compared to LPS-resistant (C3H/HeJ) mice. LPS reduced the ability of normal peritoneal macrophages to kill tetrathyridia, when co-cultured in vitro. LPS also abrogated the ability of recombinant interferon-gamma (r.IFN-gamma) to enhance macrophage larvicidal activity. These in vitro findings were confirmed in vivo. Daily intraperitoneal administration of LPS, at low concentration, caused a 4-fold increase in parasite burden in the liver, while r.IFN-gamma at optimal concentration reduced parasite burden by 57%. Post-infection macrophages have previously been shown to be refractory to cytokine-activation for larval killing. In this report, we conclude that (1) this refractoriness may be due to the presence of undetoxified endotoxin on post-infection macrophages and (2) endotoxin may reduce host resistance by abrogating effector macrophage response to IFN-gamma.

Macrophage colony‐stimulating factor gene transfer into tumor cells induces macrophage infiltration but not tumor suppression

“…Mice which had received either J558-MCSF or J558L cells the day before were injected once a day for 20 days with IFN-y (between 100 and SO00 unitdinjection) and/or LPS (100 ng or 1 pg). Both reagents have been shown to be systemically effective when applied at these concentrations [18] and we could confirm the systemic effect of IFN-y in our experimental setting. In accordance with reports by others [19], daily i.p.…”

Immunity and immune modulation elicited by the larval cestode Mesocestoides vogae and its products

“…Th1-immune responses have been reported as larvicidal for tissue-dwelling helminths, therefore to overcome the type-1 immune response is necessary for establishment of the long-term infection (2,12,14,30). However, dysregulated inflammatory responses might be analogically detrimental to the host (31).…”

“…It has been reported that IFN‐γ injections have larvicidal potential in mice. From this, a critical role for a Th1‐immune response in limiting parasite burden had been suggested although host IFN‐γ production has not been convincingly analyzed . In contrary, a persistently high pro‐inflammatory immune response was found to be associated with increased host lethality during M. vogae infection .…”

In vitro culture of Mesocestoides corti metacestodes and isolation of immunomodulatory excretory–secretory products

“…, highlighting the relevance of our observation in the general understanding of the host immunosuppression by metacestodes. Given the host protective role of IFN‐γ during experimental infection with M. corti tetrathyridia and considering the control of IFN‐γ production by dendritic cell‐derived IL‐12 , the limitation of BMDC production of IL‐12 by M. corti tetrathyridia should be beneficial to the parasite as it should consequently limit the host IFN‐gamma mediated‐inflammatory and larvicidal response .…”