EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells

Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention. Author summaryHuman cytomegalovirus (HCMV) belonged to beta-human herpesvirus is a ubiquitous pathogen causing congenital infection and relating to morbidity and mortality in immunocompromised transplant patients. Moreover, HCMV has been demonstrated to promote the progression of glioblastoma, the most common and aggressive primary brain tumor. Many studies highlighted the inevitable relationship between HCMV and glioblastoma. But the underlying mechanism of HCMV infection of glioblastoma cells has not been fully demonstrated. Here we found that EphA2, a member of receptor tyrosine kinases (RTKs) family, played a crucial role in HCMV infection of glioblastoma cells. Our research suggests that EphA2 mediates the infection of HCMV by interacting with glycoproteins gH/gL/gO displaying on the surface of HCMV virion. We find that anti-EphA2 antibody and 2,5-dimethylpyrrolyl benzoic acid derivatives can block HCMV infection in glioblastoma cells, while 2,5-dimethylpyrrolyl benzoic acid derivatives can block HCMV infection in GBOs in a dose-dependent manner, indicating that the strategy of developing an anti-HCMV drug targeting EphA2 is feasible. Our findings may assist future studies striving for a better understanding of how HCMV infects glioblastoma cells and for potential new targets of innovative antiviral strategies.

Automated summary

This study found that EphA2 is a crucial cell factor associated with human glioblastoma and correlated with poor prognosis. Furthermore, EphA2 was shown to mediate HCMV infection of glioblastoma cells through binding to HCMV gH/gL complex. Therefore, EphA2 could be a potential target for intervention in HCMV infection.