Research Overview
Molecular mechanisms of paramyxovirus entry and pathogenesis
RESEARCH TOPICS Summary The laboratory's research centers on molecular pathogenesis of human paramyxoviruses: parainfluenza virus type 3, and recently also the emerging pathogen Hendra virus. Parainfluenza virus is an important cause of lower respiratory tract infections in children, including croup and bronchiolitis, and there are currently no vaccines or antiviral agents for these diseases. Hendra virus is a highly fatal paramyxovirus which is a potential agent of bioterrorism. We are interested in how these viruses enter cells by fusing with the cells' envelope, and in how we might interfere with this viral entry process. Both the parainfluenza and Hendra projects are funded by investigator-initiated NIH grants.Parainfluenza virus: The Moscona laboratory has identified the role of the parainfluenza virus receptor-binding protein hemagglutinin-neuraminidase (HN) in the virus-induced fusion process whereby all paramyxoviruses enter host cells. HN's receptor binding is the critical first step towards HN's role in fusion promotion, and leads to activating or "triggering" of the fusion protein (F) to mediate fusion. Our parainfluenza projects focus on the molecular mechanisms whereby HN carries out its roles in the viral life cycle and in pathogenesis in the lung. Ongoing studies have led to novel antiviral strategies that are now being tested, and to understanding mechanisms of resistance to antiviral compounds. The role of HN in pathogenesis of lung disease in vivo is being studied in a human airway epithelial cell model. Our group showed that mutations in HN that alter HN-receptor interaction (but do not affect replication) lead to dramatic differences in the disease in a small animal model of illness, and these differences are reflected in the pathogenesis in the human airway. We are determining how HN's receptor affinity, its receptor-cleaving, or its F-triggering activities determine its virulence in the lung. Hendra virus: In the Hendra virus projects, we apply our strategies for the study of paramyxovirus entry and fusion to an emerging and potentially fatal paramyxovirus that is viewed as a potential bioterrorism agent. For Hendra virus, the receptor binding protein (G) is required in order for the F protein to mediate fusion. Hendra G binding to receptor, like parainfluenza virus HN binding to sialic acid, "triggers" F protein to mediate fusion. The study of the mechanism of triggering/activation of F protein in Hendra virus should lead to strategies for interfering with this key step in viral entry. Lab OrganizationThe Moscona lab is focused around the interdisciplinary theme of virus-host interactions. Projects draw from strategies and methods of molecular biology, cell biology, biophysics, immunology and virology. Each student and postdoc has their own project, but the projects are inter-related in ways that lead to constant communication and contributions to each other's development. The lab collaborates with researchers at Cornell and other institutions, and these collaborations are expanding as we develop in the areas of computational modeling of HN-ligand interactions, structure-function relationships of HN, chemical engineering of novel antiviral compounds, and medically relevant models of lung disease. Past contributions and future developmentsThis lab is best known for identifying critical roles of the parainfluenza virus receptor binding protein in activating the fusion process during entry. This key aspect of the entry/fusion process for parainfluenza virus has been found to apply to the other paramyxoviruses as well. By identifying alterations in the receptor binding protein HN that lead to defects in activating F, we have identified potential targets for interfering with the triggering process. We are developing strategies that use the 3D structure of the HN molecule, and computational screening, to identify molecules that may interact with an HN active site and alter F-triggering. For Hendra virus, we are moving forward to understand how the receptor-binding protein G triggers the Hendra virus fusion and entry process. We are also implementing several strategies to identify small molecules that will interfere with either the G-F interaction or the conformational change in F to fusion-readiness, in order to prevent entry of this pathogen into cells.
