CD155 as a Therapeutic Target in Alveolar Echinococcosis: Insights from an E. multilocularis Infection Mouse Model

Xue Zhang¹Liang Li²Tao Sun²Ning Yang¹Hui Liu¹Jin Chu¹Junlong Xue²GUODONG LYU¹Tuerganaili Aji^3*Xiaojuan Bi^1*Renyong Lin^1*

• ¹Clinical Medical Research Institute, Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases, Xinjiang Medical University, Urumqi, China
• ²Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases, Xinjiang Medical University, Urumqi, China
• ³Department of Hepatobiliary and Hydatid Diseases, Digestive and Vascular Surgery Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China

Introduction: Alveolar echinococcosis (AE) is a life-threatening zoonotic parasitic disease caused by the metacestode form of Echinococcus multilocularis (E. multilocularis), characterized by granulomatous lesions and liver fibrosis. Immune exhaustion is the main mechanism by which E. multilocularis evades host immune responses and sustains long-term parasitism. Although cluster differentiation 155 (CD155) is recognized as an immune checkpoint molecule, its specific role and mechanism in AE remain unclear. Methods: The E. multilocularis infection mouse model 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. Hematoxylin and eosin staining was used to evaluate pathological changes.Results: In E. multilocularis-infected group, we observed a significant upregulation of CD155 expression on hepatocytes adjacent to the lesions. Furthermore, we identified a notable impairment in the functionality of CD4 + and CD8 + T cells, accompanied by an enrichment of exhausted TIGIT + cells in the vicinity of CD155 + cells. Moreover, CD155 expression was significantly upregulated on hepatocytes co-cultured with metacestode vesicles in vitro. Notably, CD155 knockout in hepatocytes within the E. multilocularis infection mouse model reversed the exhaustion state in CD4 + and CD8 + T cells. Conclusions: In E. multilocularis infection mouse model, excretory/secretory products from metacestode vesicles upregulated CD155 expression in hepatocytes, thereby sustaining an immunosuppressive microenvironment. Hepatocyte-specific knockout of CD155 reversed immune exhaustion and significantly reduced lesion number and size. These findings establish CD155 as a promising therapeutic target for E. multilocularis infections.