Characterization of Herpes simplex virus internalization into keratinocytes and fibroblasts

• Applicant: Professorin Dr. Dagmar Knebel-Mörsdorf
• Subject Area: Virology
• Term: from 2007 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 51729173

Herpes simplex viruses type 1 (HSV-1) are ubiquitous human pathogens which enter their host via epithelia of skin, mucosa or cornea. How the virus invades tissue and overcomes the protective barrier provided by the epithelia to reach its receptors and initiate infection is still an open question. As epidermal keratinocytes represent the primary entry portals for HSV-1, we aim to understand which signaling pathways and receptors are involved in entry of HSV-1 into epidermis and what are the cellular mechanisms underlying internalization into keratinocytes. During the last funding period we demonstrated the major but not exclusive role of nectin-1 as receptor for HSV-1 to enter both murine epidermis and dermal fibroblasts. Herpesvirus entry mediator (HVEM) was identified as an alternative receptor, which had a more limited role in epidermis and also acted less efficiently than nectin-1 in dermal fibroblasts. HSV-1 uptake was shown to require the cellular GTPase dynamin and host cholesterol. From electron microscopy studies we concluded that viruses are internalized both by fusion of the viral envelope with the plasma membrane and via endocytic vesicles. In the current proposal we plan to characterize the underlying mechanisms of dynamin-dependence, and the functional significance of endocytic uptake. We also aim to identify pathways that allow the virus to reach its receptors in tissue. Taken together, our studies will dissect the mechanisms which HSV-1 uses to enter its natural target cells and will be important for a better understanding of how viruses invade tissue in vivo.

• DFG Programme: Research Grants