Ted C. Pierson, Ph.D.
Chief, Viral Pathogenesis Section
Description of Research Program
Flaviviruses are a group of positive-stranded RNA viruses that have a global impact due to their widespread distribution and ability to cause disease in humans and economically important domesticated animals. Several members of this genus, such as dengue virus and West Nile virus, are considered emerging or re-emerging pathogens because the incidence of human infection and disease has increased at an alarming rate. An urgent need exists for the development and implementation of safe and efficacious vaccines for flavivirus infection.
Flavivirus virions are composed of a single copy of an 11 kb genomic RNA of positive polarity, the capsid protein (C), a lipid envelope derived from the endoplasmic reticulum, and two envelope glycoproteins: envelope (E) and pre-membrane/membrane (prM/M). Our understanding of how the envelope proteins of flaviviruses bind cells and orchestrate the complex process of lipid mixing and fusion is incomplete. The primary focus of our laboratory is to understand how these proteins mediate virus assembly and entry. Two ongoing projects include the following:
Interaction between flavivirus virions and the host cell. The cell biology of flavivirus entry is poorly understood. A simple model to describe the mechanism of flavivirus entry involves the interaction of virions on the surface of target cells with one or more cellular receptors. These interactions would trigger access to the endocytic pathway via clathrin-mediated endocytosis, where fusion occurs in a pH-dependent fashion. However, several lines of evidence suggest that the engagement of a cellular “receptor” is not required to mediate fusion during virus entry, and that the flavivirus machinery is primed for fusion solely upon exposure to an acidic environment. These important findings raise several considerations, including the role of, and requirements for, specific cellular proteins during virus entry. Our goal is to identify and investigate the function of cellular factors that play a role in the early steps of the virus entry pathway.
Antibody-mediated neutralization and enhancement of flavivirus infection. Structural and cryo-electron microscopy studies reveal that the surface of the flavivirus virion is composed of a highly ordered icosahedron of 180 E proteins. The generation of antibodies capable of binding to this array of viral proteins and blocking infection is an important aspect of the immune response and a goal of vaccine development. However, under some circumstances, the presence of antibodies can also increase the efficiency of viral infection. This antibody-dependent enhancement (ADE) of infection has been linked to a more severe clinical outcome of dengue virus infection.
The possibility that immunization may elicit antibodies capable of enhancing infection poses a significant challenge for the development of flavivirus vaccines, and highlights the importance of understanding not only the magnitude, but also the breadth, specificity, and persistence of humoral immunity following vaccination. In this regard, my laboratory is investigating the mechanisms of antibody-mediated neutralization and ADE with the goal of understanding the biochemical and cellular factors that determine the outcome of the interaction of flavivirus particles with antibody.
Research Group Members
Postdoctoral Fellows: Camilo Ansarah Sobrinho, Ph.D.; Christiane Jost, Ph.D.; Steevenson Nelson, Ph.D.
Research Technician: Qing Xu, B.S.
Selected Publications
(View list in PubMed.)
Pierson TC, Xu Q, Nelson S, Oliphant T, Nybakken GE, Fremont DH, Diamond MS. Stoichiometric requirements for antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host & Microb., in press.
Oliphant T, Nybakken GE, Engle M, Xu Q, Nelson CA, Sukupolvi-Petty S, Marri A, Lachmi BE, Olshevsky U, Fremont DH, Pierson TC, Diamond MS. Antibody recognition and neutralization determinants on domains I and II of West Nile virus envelope protein. J Virol. 2006 Dec; 80(24):12149-59.
Pierson TC, Sanchez MD, Puffer BA, Ahmed AA, Geiss BJ, Valentine LE, Altamura LA, Diamond MS, Doms RW. A rapid and quantitative assay for measuring antibody-mediated neutralization of West Nile virus infection. Virology. 2006 Mar 1; 346(1):53-65.
Davis CW, Nguyen HY, Hanna SL, Sanchez MD, Doms RW, Pierson TC. West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol. 2006 Feb; 80(3):1290-301.
Davis CW, Mattei LM, Nguyen HY, Ansarah-Sobrinho C, Doms RW, Pierson TC. The location of asparagine-linked glycans on West Nile virions controls their interactions with CD209 (dendritic cell-specific ICAM-3 grabbing nonintegrin). J Biol Chem. 2006 Dec 1; 281(48):37183-94.
Sanchez MD, Pierson TC, Degrace MM, Mattei LM, Hanna SL, Del Piero F, Doms RW. The neutralizing antibody response against West Nile virus in naturally infected horses. Virology. 2007 Mar 15; 359(2):336-48.
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