Biographical Sketch

Dr. Longnecker earned his bachelor's degree in cellular and molecular biology from the University of Michigan in 1982 and his PhD degree from the University of Chicago in virology in 1987 studying herpes simplex virus in Dr. Bernard Roizman's laboratory. His postdoctoral training was with Dr. Elliott Keiff at Harvard Medical School. Dr. Longnecker joined the faculty of Northwestern University in April 1993 and has over 20 years of experience in the herpesvirus field working on both herpes simplex virus and Epstein-Barr virus.  He is Director of the Viral Oncogenesis Basic Science Program at the Robert H. Lurie Comprehensive Cancer Center and Director of the Integrated Graduate Program at the Feinberg School of Medicine.

Contact Information:

Phone – 312-505-0467

Research Description

Molecular biologic and molecular genetic studies of Epstein-Barr virus (EBV) transformation of human B lymphocytes; regulation of EBV latency in vitro and in vivo using transgenic model systems; identification and role of viral and cellular factors important for virus binding, entry, and maturation from cells susceptible to EBV infection.

Research Abstract

Disease syndromes in humans caused by EBV reflect the cell types that EBV infects, being primarily of lymphoid or epithelial origin. The most notable lymphoid disease, infectious mononucleosis, is a self-limiting lymphoproliferative disease that occurs in normal adolescents upon primary infection. Children are normally able to resolve primary EBV infection with few or no symptoms. By the age of 25 most individuals are EBV seropositive. EBV is associated with a variety of hemopoietic cancers such as African Burkitt's lymphoma, Hodgkin's lymphoma and adult T-cell leukemia. EBV-associated lymphoproliferative disease occurs in individuals with congenital or acquired cellular immune deficiencies. EBV-associated lymphoproliferative disease occurs in 1 percent to 10 percent of transplant recipients and in AIDS patients. The two notable epithelial diseases associated with EBV infection are nasopharyngeal cancer, a malignancy endemic to southern China, and oral hairy leukoplakia, an epithelial hyperplasia of the lingual squamous epithelium in AIDS patients.

B lymphocytes infected in vivo or in vitro by EBV become latently infected by the virus and are driven to proliferate indefinitely. These transformed, latently infected B lymphocytes contain EBV episomes that express eight virus-encoded proteins. Six are nuclear proteins (EBNAs) and two are the integral membrane proteins LMP1 and LMP2. These eight proteins mediate latent virus infection or B lymphocyte proliferation and are being studied in our laboratory. We are most interested in LMP1 and LMP2, which besides EBNA1 (required for episome maintenance) are the two transformation-associated proteins most consistently detected in EBV-related malignancies. In addition, the LMP2 message is the only message detected in PCR analysis of B lymphocytes from individuals harboring latent EBV infections. Our current studies of LMP2 have shown that it down regulates LMP1 activation of B lymphocytes and prevents normal signal transduction through cell surface receptors. In addition, we have shown that LMP2 prevents the switch from latent infection to lytic infection following activation of the B-cell receptor in B lymphocytes latently infected with EBV. Finally, we have shown using in vivo models of EBV latent infection that LMP2 provides an inappropriate survival signal to primary B lymphocytes.  These LMP2 functions may be important for persistence of EBV in the human host. We are trying to identify LMP2-associated proteins. LMP2 associates with LMP1, Src family tyrosine kinases, the Syk tyrosine kinase, Nedd4 ubiquitin ligases, and at least four unidentified cell proteins, several of which are tyrosine phosphorylated. We are introducing site-specific mutations into LMP2, Src, and Syk to delineate amino acids critical for the protein-protein interactions between Syk, Src and LMP2 and other cell proteins. We are investigating the phenotype of EBV immortalized cell lines transformed with EBV recombinants with mutated LMP2s. This characterization includes the analysis of cell surface marker expression, in vivo growth properties in SCID mice, and activation of lytic infection following crosslinking of cell surface receptors.  Finally, we are investigating the role of LMP2 in primary EBV infections and latency in animal models of EBV pathogenesis.

Recently we have begun the investigation of certain lytic cycle genes that are important in the virus life cycle. Specifically viral genes important for virus binding, entry and maturation from susceptible cells are being studies. We hope to also identify cellular factors important for virus binding, entry and maturation from susceptible cells. Ultimately we hope our studies may provide insight for the development of novel therapeutics for the treatment of EBV-related malignancies, a better understanding of the viral life cycle in the human host, and a general understanding of signal transduction and cell growth regulation in lymphocytes.

Complete list of Dr. Longnecker's publications on PubMed web site.

Publications (Click on icons at left to link to either the full-text document or abstract)