CD155 as a therapeutic target in alveolar echinococcosis: insights from an Echinococcus multilocularis infection mouse model

Abstract

Introduction: Alveolar echinococcosis (AE) is a life-threatening zoonotic parasitic disease caused by the metacestode stage of Echinococcus multilocularis, characterized by granulomatous lesions and liver fibrosis. Immune exhaustion is the key mechanism by which E. multilocularis evades host immune responses and maintains long-term parasitism. Although CD155 is recognized as an immune checkpoint molecule, its specific role and underlying mechanism in AE remain unclear.

Methods: A mouse model of E. multilocularis infection was used to investigate the role of CD155 in AE progression. Flow cytometry, immunohistochemistry, and immunofluorescence were employed to assess CD155 expression and analyze T-cell function. In addition, liver weight, lesion size, lesion number, inflammation index, collagen deposition (via Masson staining), and stellate cell activation (via α-SMA immunohistochemistry) were statistically quantified in the CD155 hepatocyte knockout mice. Each experimental group included five mice (n = 5).

Results: CD155 expression in hepatocytes was significantly increased-approximately 2-fold compared to Sham controls-and predominantly localized near lesion sites. The infected group showed significantly reduced percentages of functional CD4⁺IFN-γ⁺, CD4⁺CD107a⁺, and CD8⁺CD107a⁺ T cells (p < 0.05), along with enrichment of exhausted TIGIT⁺ T cells adjacent to CD155⁺ hepatocytes. In vitro, CD155 expression in hepatocytes was upregulated in a dose-dependent manner when co-cultured with metacestode vesicles, reaching 1.5-fold that of the control. Notably, hepatocyte-specific CD155 knockout in infected mice restored CD4⁺ and CD8⁺ T-cell function and reduced liver damage, as indicated by decreased lesion burden.

Conclusion: In the E. multilocularis infection mouse model, excretory/secretory products from metacestode vesicles upregulated CD155 expression in hepatocytes, contributing to an immunosuppressive microenvironment and T-cell exhaustion. Targeting CD155 reverses this immunosuppression and mitigates hepatic pathology, highlighting CD155 as a promising therapeutic target for AE.

Keywords: CD155; Echinococcus multilocularis; T-cell exhaustion; alveolar echinococcosis; metacestode vesicles.

Figure 1

CD155 expression in the liver of the E. multilocularis infection mouse model. (A) H&E staining (n = 5). (B) Immunofluorescence staining of CD155 (n = 5). (C) IHC of CD155 (n = 5). (D) Statistical graphs of IHC. (E) Flow cytometry results of CD155 expression in primary hepatocytes (n = 5). (F) Statistical graphs of flow cytometry. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 2

CD155 expression correlates with T cell functional exhaustion. (A) Flow cytometry results of CD107α, IFN-γ, and granzyme B in CD4⁺ T cells (n = 5). (B) Flow cytometry results of CD107α, IFN-γ, and granzyme B in CD8⁺ T cells (n = 5). (C) Statistical graphs of flow cytometry for CD4⁺ T cells (n = 5). (D) Statistical graphs of flow cytometry for CD8⁺ T cells (n = 5). (E) Multiple immunohistochemical staining of CD155 and TIGIT (n = 5). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3

Metacestode vesicles promote CD155 upregulation in hepatocytes. (A) Schematic diagram. (B) Morphological changes from protoscoleces to hydatid cysts at different times. (C,D) Flow cytometry results of CD155 expression (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 4

Hepatocyte CD155 knockout restores T cell function. (A,B) Statistical graphs of the inflammatory index, lesion area, and total liver weights (n = 5). (C) ELISA results of granzyme B, IFN-γ, and TNF-α (n = 5). (D,E) Flow cytometry plots of CD107α, IFN-γ, and granzyme B in CD4⁺ T cells (n = 5). (F,G) Flow cytometry plots of CD107α, IFN-γ, and granzyme B in CD8⁺ T cells (n = 5). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 5

Schematic diagram of the study on the functional inhibition and targeted intervention of T cells by the interaction between liver cell CD155 and TIGIT.