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 Correction: Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry.

In the version of this Letter originally published, the authors reported on the use of 2,5-dimethylpyrrolyl benzoic acid to block Ephrin receptors. In 2011, it was reported that newly synthesized 2,5-dimethylpyrrolyl benzoic acid lacked the previously reported EphA2 antagonizing activity1. However, the purchased compound did in fact have the activity initially reported, suggesting that an uncharacterized alteration occurred during storage. The authors therefore wish to clarify that the compound used in their study should be more accurately referred to as a 2,5-dimethylpyrrolyl benzoic acid derivative. All references to 2,5-dimethylpyrrolyl benzoic acid in the Letter have now been changed to reflect this.Although 2,5-dimethylpyrrolyl benzoic acid derivatives have been reported to have off-target effects2, as do most small-molecule inhibitors, the multiple complementary methods and techniques used demonstrate that EphA2 is a key Epstein-Barr virus epithelial cell receptor. The conclusions of the study are therefore unchanged.

Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry.

Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma, 10% of gastric carcinoma and various B cell lymphomas 1 . EBV infects both B cells and epithelial cells 2 . Recently, we reported that epidermal growth factor and Neuropilin 1 markedly enhanced EBV entry into nasopharyngeal epithelial cells 3 . However, knowledge of how EBV infects epithelial cells remains incomplete. To understand the mechanisms through which EBV infects epithelial cells, we integrated microarray and RNA interference screen analyses and found that Ephrin receptor A2 (EphA2) is important for EBV entry into the epithelial cells. EphA2 short interfering RNA knockdown or CRISPR-Cas9 knockout markedly reduced EBV epithelial cell infection, which was mostly restored by EphA2 complementary DNA rescue. EphA2 overexpression increased epithelial cell EBV infection. Soluble EphA2 protein, antibodies against EphA2, soluble EphA2 ligand EphrinA1, or the EphA2 inhibitor 2,5-dimethylpyrrolyl benzoic acid efficiently blocked EBV epithelial cell infection. Mechanistically, EphA2 interacted with EBV entry proteins gH/gL and gB to facilitate EBV internalization and fusion. The EphA2 Ephrin-binding domain and fibronectin type III repeats domain were essential for EphA2-mediated EBV infection, while the intracellular domain was dispensable. This is distinct from Kaposi's sarcoma-associated herpesvirus infection through EphA2 4 . Taken together, our results identify EphA2 as a critical player for EBV epithelial cell entry.

[Clinical study of trimetazidine for myocardial protection in acute myocardial infarction].

OBJECTIVE: To assess the effect of trimetazidine as an adjunctive treatment to reperfusion therapy in acute myocardial infarction. METHODS: Sixty patients with acute myocardial infarction were randomized to receive trimetazidine (a loading dose of 60 mg followed by 20 mg 3 times daily) for 2 weeks (n = 32) or to be controls (n = 28). The loading dose was started early before the reperfusion therapy. Patients received intermittent ST-segment monitoring to assess the resolution of ST-segment deviation one hour after reperfusion therapy. Venous blood samples for measurement of malondialdehyde (MDA) and endothelin (ET-1) were taken immediately on admission and 1, 4, 8, 24 and 48 hours as well as 7 days after reperfusion. In-hospital and 3-months major adverse cardiac events were recorded. RESULTS: Blinded ST-segment analysis showed that there was a more marked return towards baseline one hour after reperfusion therapy in the trimetazidine group, than in the control group [change (7.14 +/- 3.50) mm vs (3.79 +/- 1.32) mm, P = 0.041]. The measurement of plasma MDA showed that, there was a significantly lower level in the trimetazidine group 4, 8, 24, 48 hours and 7 days after reperfusion (P < 0.05). The level of plasma ET-1 was significantly lower in the trimetazidine group 8 hours and 7 days after reperfusion (P < 0.05). There was no side effect due to trimetazidine. Clinical outcomes were similar between the two groups. CONCLUSIONS: Trimetazidine is effective for the resolution of ST-segment elevation. The effect of trimetazidine against malondialdehyde and ET-1 formation suggested that it might be the mechanism of the myocardial protection.