Overview:

The main focus of the White Laboratory is on virus entry into host cells. We also study the role of ADAM proteins in early development in collaboration with the laboratory of Dr. Douglas DeSimone.

Virus Entry Into Cells: A general paradigm has emerged for how enveloped viruses fuse with, and thereby initiate infection of, target cells. Fusion is mediated by a specific viral membrane fusion protein (e.g., the hemagglutinin of influenza virus) or a complex of viral glycoproteins (e.g., in the case of herpesviruses). In response to a fusion trigger (e.g., low endosomal pH or specific host cell receptors) the fusion protein changes conformation, exposes its fusion peptide, and binds hydrophobically to target membranes. A refolding event then brings the fusion peptide and the transmembrane domain, and their attached target and viral membranes, very close together. This leads to hemifusion and then opening of a fusion pore. Our current work is focused on characterizing novel viral entry pathways and novel fusion triggers, for example those used by Ebola virus, a highly pathogenic filovirus. We are also pursuing several approaches to identify compounds that inhibit infection by blocking virus binding to or fusion with host cells. (See Models & Figures Link for more information.)

ADAMs in Early Development: ADAMs are transmembrane proteins that contain A Disintegrin and A Metalloprotease domain. The first ADAMs were discovered in my laboratory in the early 1990s. Since that time, the ADAM family, which has 22 members in humans, has emerged as the major family of proteases responsible for ectodomain shedding, a critical process whereby bioactive molecules (e.g., EGF family members and TNF-alpha) are released from the cell surface. About half of the ADAMs are proteolytically-inactive; they therefore exert their influence by other means, perhaps by modulating cell adhesive interactions. ADAMs have been implicated in a variety of developmental and pathological processes. Our ongoing work on ADAMs, performed in collaboration with the laboratory of Dr. Douglas DeSimone, continues to probe the role of ADAMs in early development, for example in neural crest. (See Models & Figures Link for more information)