Abstract
BackgroundLarvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. The recruitment of alternatively activated macrophages (AAMs) has been observed in a variety of helminth infections, and emerging evidence indicates that AAMs are critical for the resolution of inflammation. However, whether AAMs can be induced by E. granulosus (s.l.) infection or thioredoxin peroxidase (TPx), one of the important molecules secreted by the parasite, remains unclear.MethodsThe activation status of peritoneal macrophages (PMs) derived from mice infected with E. granulosus (sensu stricto) was analyzed by evaluating the expression of phenotypic markers. PMs were then treated in vivo and in vitro with recombinant EgTPx (rEgTPx) and its variant (rvEgTPx) in combination with parasite excretory-secretory (ES) products, and the resulting activation of the PMs was evaluated by flow cytometry and real-time PCR. The phosphorylation levels of various molecules in the PI3K/AKT/mTOR pathway after parasite infection and antigen stimulation were also detected.ResultsThe expression of AAM-related genes in PMs was preferentially induced after E. granulosus (s.s.) infection, and phenotypic differences in cell morphology were detected between PMs isolated from E. granulosus (s.s.)-infected mice and control mice. The administration of parasite ES products or rEgTPx induced the recruitment of AAMs to the peritoneum and a notable skewing of the ratio of PM subsets, and these effects are consistent with those obtained after E. granulosus (s.s.) infection. ES products or rEgTPx also induced PMs toward an AAM phenotype in vitro. Interestingly, this immunomodulatory property of rEgTPx was dependent on its antioxidant activity. In addition, the PI3K/AKT/mTOR pathway was activated after parasite infection and antigen stimulation, and the activation of this pathway was suppressed by pre-treatment with an AKT/mTOR inhibitor.ConclusionsThis study demonstrates that E. granulosus (s.s.) infection and ES products, including EgTPx, can induce PM recruitment and alternative activation, at least in part, via the PI3K/AKT/mTOR pathway. These results suggest that EgTPx-induced AAMs might play a key role in the resolution of inflammation and thereby favour the establishment of hydatid cysts in the host.
Highlights
Larvae of Echinococcus granulosus dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival
Echinococcus granulosus (s.s.) infection induces peritoneal macrophages (PMs) to differentiate into an alternatively activated phenotype To determine whether E. granulosus (s.s.) infection induces the alternative activation of PMs, PMs were collected by adherence from mice 6 months after infection with E. granulosus (s.s.) microcysts
We subsequently examined the expression of classically activated macrophages (CAMs) and activated macrophages (AAMs) (CD206) markers in these PM subsets, and the results showed that compared with the administration of phosphate-buffered saline (PBS), the delivery of ES products and recombinant EgTPx (rEgTPx) or infection with PSCs significantly increased the percentage of CD206+ macrophages in both the large peritoneal macrophages (LPMs) (F(3 16) = 41.22, P < 0.0001) and small peritoneal macrophages (SPMs) (F(3, 16) = 251.7, P < 0.0001) subsets and reduced the percentage of iNOS+ macrophages in the SPM subset (F(3, 16) = 8.9, P = 0.0008) (Figs. 2c, 3c and Additional file 4: Figure S3)
Summary
Larvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. Recent studies have shown that the intraperitoneal injection of PSCs into mice induces a significant cellular inflammatory response at the early stage that involves macrophage, eosinophil, neutrophil and lymphocyte infiltration [5, 6], whereas at the cyst establishment stage, the parasite induces inflammatory cell infiltration but generally does not elicit a severe inflammatory response [2, 7]. This phenomenon indicates that E. granulosus (s.l.) has the ability to skew the peritoneal immune response away from a proinflammatory response and toward an anti-inflammatory response to avoid clearance. The mechanism through which the parasite modulates the host inflammatory response to favor its establishment in the host is unclear
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