![Margaret Kielian](https://assets.montefioreeinstein.org/profiles/images/7896-margaret-kielian.jpg)
Margaret Kielian, Ph.D.
- Professor, Department of Cell Biology
- Samuel H. Golding Chair in Microbiology
Area of research
- Areas of research: Virus entry into host cells and virus membrane fusion; virus assembly and exit; virus genome encapsidation; virus protein structure and function; virus cell-to-cell transmission
Phone
Location
- Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Chanin Building 515A Bronx, NY 10461
Research Profiles
Professional Interests
All enveloped viruses use the essential steps of membrane fusion to enter a host cell, and membrane budding to exit. Molecular information on the entry and exit processes is critical to understanding the lifecycle of enveloped viruses and how they exploit the host cell machinery, and as a key model for cellular membrane fusion and budding reactions.
Our research focuses on the molecular mechanisms of virus entry and exit using alphaviruses and the closely related virus Rubella virus, and flaviviruses such as dengue virus. The flaviviruses and alphaviruses include many important human pathogens such as dengue, Zika, and Chikungunya viruses, which cause millions of human infections each year. There are no vaccines or antiviral therapies for most of these viruses, and new strategies are urgently needed.
Alphaviruses, Rubella virus and flaviviruses enter cells by endocytic uptake and then fuse their membrane with the endosome membrane in a reaction triggered by the low pH of the endocytic vesicle. The membrane fusion proteins of these viruses are structurally related proteins and refold during fusion to a homotrimer conformation that mediates virus fusion and infection. Recent studies have also shown that structurally similar proteins are expressed in plants and in many animals, where they mediate cell-cell fusion of gametes and during development.
Many important questions on the molecular mechanism of membrane fusion remain for both viruses and cells. Little is known about the mechanism and structural features of fusion protein insertion into the target-membrane. We are also investigating the pH-dependent control mechanisms for the Rubella virus fusion reaction.
During alphavirus and flavivirus biogenesis, a companion protein forms a closely-associated dimer with the fusion protein, and protects it from low pH and premature fusion during exocytic transport. This companion protein must then dissociate to permit virus fusion. The pH protection mechanisms for many other viruses are unknown, and we are using Rubella virus as a system to define novel mechanisms of pH protection.
Alphaviruses exit by budding through the plasma membrane of the infected host cell. Little is known about alphavirus assembly and budding, although it is clear that these processes are highly regulated to produce organized virus particles of high specific infectivity. How does this happen and what are the roles of cellular and viral factors? We seek to determine how the internal viral RNA-capsid core is assembled, how the virus excludes host RNAs, and how nucleocapsid assembly can be inhibited by small molecules. We are using a novel capsid protein retrieval strategy to identify and characterize host factors involved in alphavirus nucleocapsid assembly. We have developed fluorescently tagged alphaviruses to follow virus assembly and budding in real time in infected cells. We are investigating how alphaviruses spread from cell to cell, a process that protects the virus from antibody neutralization. The cell plasma membrane and cytoskeletal network are dramatically remodeled during budding and we are defining the mechanisms and signaling pathways that mediate remodeling.
Our lab uses a wide variety of approaches including molecular biology, virus genetics, protein biochemistry, live cell imaging, cell biology, and structural biology. Potential research projects include: investigation of specific molecules involved in cell-to-cell virus transmission, use of fluorescently tagged viruses to follow steps in virus assembly and budding, characterization of the role of cellular factors in virus assembly and exit, use of virus mutants to characterize specific steps in fusion and pH protection.
Selected Publications
Please see PubMed link on the upper right.