BIOE Seminar Series: Understanding Coronavirus Host Cell Entry Machinery
Friday, September 17, 2021
9:00 a.m.-10:00 a.m.
Dr. Susan Daniel
Fred H. Rhodes Professor of Chemical Engineering
William C. Hooey Director of the Robert Frederick Smith School of Chemical and Biomolecular Engineering
Leveraging our Fundamental Understanding of the Coronavirus Host Cell Entry Machinery to Stop Virus Infection
The coronavirus disease 2019 (COVID-19) pandemic has focused attention on the need to develop effective therapies against the causative agent, SARS-CoV-2, and any pathogenic coronaviruses (CoV) yet to emerge. Focusing on steps in the CoV replication cycle, in particular the entry steps involving membrane fusion that are vulnerable to inhibition by broad-spectrum or specific antiviral agents, is an astute choice because of the conserved nature of the fusion machinery and mechanism across the CoV family. For coronavirus, entry into a host cell is mediated by a single glycoprotein protruding from its membrane envelope, called spike (S). Within S, the region that directly interacts with the membrane is called the fusion peptide, FP. It is the physico-chemical interactions of the FP with the host membrane that anchors it, thus enabling the necessary deformations of the membrane that lead to delivery of the viral genome into the cell when a fusion pore opens. Biomolecular engineers contribute to this knowledge by leveraging understanding of thermodynamics, kinetics, and intermolecular interactions to describe FP interactions with the host membrane at the most fundamental molecular level that later facilitates the development of strategies to limit those interactions to stop the spread of infection. In this talk, I will focus on our work on understanding the impact of calcium ions on CoV infection. Using cell infectivity experiments, directed mutagenesis approaches, biophysical assays, and spectroscopic methods, we found that calcium ions stabilize the fusion peptide structure during its conformational change that then allows its insertion into the host membrane, resulting in increased lipid ordering in the membrane. This lipid ordering precedes membrane fusion and has been shown to correlate with increased fusion activity, as higher extents of fusion are observed as calcium concentration increases, aligned with higher levels of infection in the presence of calcium. Finally, depletion of calcium ions leads to structure and activity changes that correlate well with in vitro experiments using calcium-chelating drugs. Under these conditions, cell infection drops, pointing to the possibility of such drugs as therapeutic interventions. Inspired by these results, we investigated FDA-approved calcium channel blockers for off-target application in protecting lung cell infection using live virus. Finally, I will introduce a new platform under development that replicates the entry process of the virus for the purpose of developing new drugs against the functional aspects of the spike protein using a biomembrane bioelectronics device.
About the Speaker - Susan Daniel
Susan Daniel is the Fred H. Rhodes Professor of Chemical Engineering and the William C. Hooey Director of the Robert Frederick Smith School of Chemical and Biomolecular Engineering at Cornell University. She leads a research group working to understand cell membrane functions and the biological processes that happen within them. Her group pioneered the use of “cell-free” biomembrane platforms for re-creating cellular processes on chip and for conducting biophysical studies of mammalian, bacterial, and plant cell membranes. Much of the work they do has an impact in human health or advancing biotechnologies for the good of humankind. Her team is most well known for their work in understanding virus entry and infection, in particular, the protein fusion machinery of coronavirus. Susan and her group’s research has garnered a number of scientific recognitions. She is the recipient of a National Science Foundation CAREER award (2011), the Schwartz Life Sciences award (2016), the College of Engineering’s Research Excellence Award at Cornell University (2017), and in 2020, Susan was elected as an AAAS fellow.
Susan is the current co-chair of the 2022 Gordon Research Conference in Bioanalytical Sensors. Four current students hold NSF Graduate Research Fellowships, several have been honored with prestigious Sloan Fellowships, others participate in esteemed NIH-funded training grants, and one is a HHMI Gilliam Fellow.
Susan believes that greater access to education for all leads to more diverse perspectives and greater creativity, essential for impactful research and social equity. Susan served as the Director of Graduate Studies in her department from 2016-2019, during which her department had the most diverse classes in its history, over the national average, and reaching US demographic parity. Susan was the faculty advisor for the Chemical and Biomolecular Engineering Graduate Women’s Group (CBE Women) from 2008-2020, a group focused on professional development and leadership opportunities for graduate students. In 2018, she founded CBE’s Diversity and Inclusion Program to foster inclusive practices and to build an enriching environment for all - from the classroom to the lab. Susan has been honored for her leadership in these areas with the Denice Denton Emerging Leader Award (2012), the Zellman Warhaft Commitment to Diversity Award (2014), and the Alice H. Cook Award (2015). She was also selected to the shortlist of the 2016 international GEDC Airbus Diversity Award for her work in creating and advising the annual outreach program, WOMEN, for 10th grade girls and their families from rural upstate NY.
Susan serves as the faculty-in-residence for Balch Hall: the all-women, freshmen residence. In this role she provides educational programming and intellectual engagement activities for a hall of 445 women. Balch Hall counts Justice Ruth Bader Ginsburg among its alumnae and Susan considers it an honor to lead Balch now and positively influence today’s young women to set their sights high and aspire to impactful life pursuits, perhaps inspiring tomorrow’s Supreme Court justice, leading tech entrepreneur, or president!
Susan holds a BS, MS and PhD from Lehigh University and conducted her post-doctoral work at Texas A&M University in the Department of Chemistry. She considers it an honor to share authorship with the late Nobel Laureate Professor Pierre de Gennes on one of her early publications in graduate school, which set her onto the pathway of becoming an academic professor.
In Susan’s free time she enjoys getting back to nature and hiking. She has completed 200 miles of GR5 trail through the French Alps, has hiked through the wilds of Montana and seen grizzly bear and moose at close range, and enjoys climbing the mountains of the high peak area in the Adirondack Park in her home state of New York.