Abstract
Purpose: To investigate the mechanism by which natural killer (NK) cells are compromised by infection with Echinococcus multilocularis in patients with alveolar echinococcosis (AE).
 Methods: NK cells from AE patients and healthy individuals were measured by flow cytometry and quantitative real-time polymerase chain reaction (PCR) to identify the frequency of different types of NK cells and assess their function. E. multilocularis cyst fluid (EMF) was applied to human monocytic leukaemia cells (THP-1 cells) to assess its effect on their differentiation. In a co-culture system with NK and EMF-THP-1 cells, the function of NK cells were analyzed by enzyme-linked immunosorbent assay (ELISA) with or without antibody against KIR2DL1.
 Results: Blood from AE patients had fewer CD56low NK cells (p < 0.01) with decreased production of IFN-γ and granzyme B due to the elevated expression of KIR2DL1 (p < 0.001). Treatment of THP-1 cells with EMF induced a tolerogenic phenotype upon activation. Incubation of these EMF-THP-1 cells with NK cells isolated from AE patients significantly impaired the cytotoxic function of NK cells, but this effect was largely blocked by an anti-KIR2DL1 antibody (p < 0.001).
 Conclusion: E. multilocularis modulates infection macrophages to induce NK cell dysfunction via interaction with KIR2DL1. These results provide a new insight into the mechanisms of parasitic infection-induced dysfunction of NK cells, and may be helpful for the development of therapeutic strategies for the treatment of alveolar echinococcosis.
Highlights
Alveolar echinococcosis (AE) is a group of diseases induced by the larvae of the parasitic tapeworm Echinococcus multilocularis (E. multilocularis) [1,2]
Natural Killer cells from the blood of patients infected with E. multilocularis functioned abnormally and showed increased expression of KIR2DL1 compared to cells from blood of noninfected controls
Effect of E. multilocularis cyst fluid (EMF) treatment on the function of macrophages and their phenotype There were significantly lower levels of the proinflammatory cytokines IL-1β and IL-6 levels in the THP-1 cells cultured with EMF than those cultured with serum from normal humans, but IL10 and transforming growth factor (TGF)-β1 levels were greater in the EMFtreated cells (Fig. 2A)
Summary
Alveolar echinococcosis (AE) is a group of diseases induced by the larvae of the parasitic tapeworm Echinococcus multilocularis (E. multilocularis) [1,2]. Killer-cell immunoglobulin-like receptors (KIRs) are primarily expressed on the cell surface of NK cells, and on a small number of T cells [10]. These receptors can interact with major histocompatibility (MHC) class I molecules to regulate the “master switch” of NK cells. During E. multilocularis infection, macrophages are ideally poised, spatially and temporally, to contact the parasite [14]. Based on this background, it was hypothesized that infection by E. multilocularis altered macrophages, and in turn, had an impact on NK cells
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