The role of Ephrin-A2 receptor-tyrosinkinase in Kaposi sarcoma-associated herpesvirus infection

• Applicant: Privatdozent Dr. Frank Neipel
• Subject Area: Virology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244312816

Kaposi sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus 8 (HHV-8), is the causative agent of Kaposi sarcoma (KS) and two lymphoid malignancies. Entry of a herpesvirus into a cell is a multi-step process involving several viral glycoproteins and cellular receptors. Recently, we identified the first receptor for KSHV glycoprotein H and L (gH/gL): Ephrin receptor-tyrosinkinase A2 (EphA2). EphA2 is crucial if not absolutely essential for the infection of endothelial cells which are the origin of KS. EphA2 is not only a receptor for KSHV; it is also known to contribute to oncogenesis and neo-vascularization. Amongst others, EphA2 interacts with molecules and triggers signaling cascades that are known to be involved in KSHV entry. EphA2 is highly expressed in many solid tumors. We showed that this is the case in KS, too. Interestingly, whereas EphA2 is upregulated in latently KSHV infected KS tissues, reactivation of KSHV lytic replication is accompanied by a marked reduction of EphA2 expression. The mechanism(s) of EphA2 expression regulation are essentially unknown. We showed that the KSHV transcription factor RTA is sufficient for EphA2 downregulation upon KSHV reactivation. In summary, EphA2 is likely to be a key molecule in KSHV infection that contributes to KS pathogenesis. However, the step(s) of KSHV entry in which EphA2 is involved have been poorly defined so far The goals of this project are: 1. Identification of the steps in the entry process that are regulated by EphA2, 2. Dissection of the intracellular domains of EphA2 involved in KSHV entry/infection, 3. identification of the signaling pathways triggered by EphA2 which are relevant for KSHV entry. 4. Identification of the mechanisms (transcriptional or post-transcriptional) of EphA2 expression-regulation by RTA. It is likely that the analysis of EphA2 involvement in KSHV entry and its regulation by KSHV will not only be important for the understanding of KSHV biology and KS pathogenesis but will also shed light on the functions of EphA2 in cancer in general.

• DFG Programme: Research Grants