Evaluation of the role and therapeutic potential of glycans in flavivirus NS1 mediated endothelial permeability and vascular leak
Eva Harris, Professor
Public Health; Div of Infectious Diseases and Vaccinology
Applications for Spring 2025 are closed for this project.
Dengue (DENV) and Zika (ZIKV) flaviruses are mosquito-borne viruses that are major medical and public health problems worldwide. DENV causes the most prevalent mosquito-borne viral disease of humans, and severe cases manifesting vascular leakage can be fatal. Nonstructural protein 1 (NS1) is a flaviviral protein that participates in viral RNA replication and in its secreted form plays important roles in host immune evasion and viral pathogenesis. We and others recently described novel roles for NS1 in directly triggering endothelial barrier dysfunction and inducing inflammatory cytokine production from human immune cells, contributing to vascular leak in vivo. Additional work has demonstrated that distinct flavivirus NS1 proteins bind differentially to glycans, particularly heparan sulfate and chondroitin sulfate, on the cell surface. Currently, we are investigating candidate glycans (heparan sulfate, chondroitin sulfate, hyaluronic acid, sialic acid) in key human endothelial cells (lung, brain, umbilical cord, liver) to determine their role in tissue tropism of flavivirus NS1. Additionally, we are evaluating the in vitro and in vivo efficacy of exogenously added glycans against NS1-mediated pathogenesis, as well as against DENV and ZIKV infection in vivo. We will select the most promising inhibitor(s) of NS1-induced pathophysiological pathways of DENV and ZIKV based on prevention of endothelial dysfunction in vitro and investigate their mechanism of action.
Role: The URAP student will work under the direct supervision of a senior graduate student in Dr. Eva Harris’ laboratory, Vanessa Jimenez, and be expected to work a minimum of 12-15 hours per week and commit to at least one year, ideally including the summer of 2020. This requires regular work on weekdays that may extend beyond after 5pm and occasional work on weekends or as arranged with the postdoctoral researcher. Skills learned will include but not be limited to cell culture, ELISA, and immunofluorescence microscopy. The URAP student is also expected to attend weekly research meetings and maintain detailed records of the work performed. The student is expected to complete the assignments in a timely manner, maintain open communication with other members of the research group and with the research coordinator, ask questions when he/she needs help or guidance, and actively ensure (through communicating with the research coordinator) that he/she is getting the experience expected from the URAP program.
Qualifications: The apprentice must be at a sophomore or junior level and have a strong interest in cell biology and infectious disease. Experience with sterile technique, cell culture, and microscopy is preferred. Other requisites are being highly motivated and having an enthusiastic scientific spirit and the desire to develop independent thinking.
Day-to-day supervisor for this project: Vanessa Jimenez-Posada, Staff Researcher
Hours: 12 or more hours
Related website: https://www.harrisresearchprogram.org
Biological & Health Sciences