In some ways, the Ebola virus operates like a vampire; only after it is politely invited in to a host cell does it take up the task of destroying everything in its path.
The virus uses the everyday function of endocytosis--the taking in of matter by a living cell--to gain entry, first attaching to the outer wall before a vesicle forms to draw it into the cell.
In a new study supported by the National Institutes of Health, researchers at Lehigh University seek to elucidate quantitatively--for the first time--the biomechanical mechanism of Ebola-host cell interaction, providing potential new targets for antiviral drug development.
"It is not hyperbole: the outbreak of an Ebola virus epidemic poses a major threat to the entire world," says Frank Zhang, assistant professor in the Departments of Bioengineering and of Mechanical Engineering and Mechanics at Lehigh University and principal investigator on the project. "Yet, because the mechanisms of the actual infection process remain obscure, there is still no specific treatment or vaccine for this dreaded disease."
While Ebola-host cell attachment has been shown to depend on the molecular biomechanics of interaction between receptors on the cell surface and the outer coat of the virus, the quantitative understanding essential for guiding the development of therapies has yet to be developed, says Anand Jagota, co-PI on the project, founding chair of the Department of Bioengineering and Professor of Chemical and Biomolecular Engineering.
The Lehigh team supporting the project, Biomechanics of TIM protein-mediated Ebola virus-host cell adhesion, pairs Jagota's expertise in computational molecular adhesion mechanics with Zhang's focus in mechanosensing--how cells sense and respond to mechanical stimuli. The project, supported by the National Institute of Allergy and Infectious Diseases through a grant totaling nearly a half million dollars over a three year period, formally launched in January of 2018.
According to the team, recent work by other researchers has established the importance of the T-cell immunoglobulin and mucin (TIM) family of proteins in the virus' ability to attach to a cell, specifically the geometry and mechanical properties of TIM's so-called mucin-like stalk domains (MLD). Jagota and Zhang intend to use their skills in experimental and theoretical molecular biomechanics to build upon these recent findings.
"Our hypothesis is that quantitative knowledge about the length, rigidity and charge of MLD can be used to predict conditions for Ebola's attachment," says Jagota. "Through this study, we hope to provide new pharmacological targets and aid in the development of much-needed antiviral therapeutics for the prevention and treatment of Ebola."
A winning partnership
The new project takes advantage of Zhang's capabilities in single-molecule force spectroscopy, and those of Jagota in computational molecular adhesion mechanics, to address the problem of establishing quantitative understanding of the molecular, cellular, and biomechanical mechanisms of Ebola attachment to a host cell.
Jagota has been a leading researcher in biomaterials, biomechanics, and nanobiotechnology for close to three decades. His group also works on properties, processing, and modeling of DNA interactions with nanomaterials, specifically on its hybrids with carbon nanotubes, and has interests in nanomechanics, biomechanics, adhesion and friction. Jagota has authored more than 150 refereed articles. He maintains strong collaborations with academic colleagues and participates closely in developing the Ph.D. dissertations of many students. Before joining Lehigh, Jagota was engaged in similar research endeavors at the DuPont Corporation.
Zhang leads an interdisciplinary Lehigh research team that integrates physics, immunology and biology. His team specializes in mechanosensing, with efforts focused on the biomechanical mechanisms of protein folding, conformational change and protein-protein interactions. Zhang's group is also active in the development and application of single-molecule force spectroscopic approaches to study cell adhesion and migration.
In the lab, Zhang uses single molecule force spectroscopy to monitor, manipulate and measure mechanical forces. With optical tweezers, he exerts minute forces onto samples and records the dynamics of protein conformation and mechanical response in real time. The team studies integrin, a protein molecule that serves as a mechanical sensor to transmit signals across the cell membrane. The team is also designing a polymer that mimics a blood-clotting molecule called the von Willebrand Factor (vWF), which binds with platelets during rapid blood flow. The ultimate goal of the team's work is to develop a mechanically switchable nanodevice for targeted drug therapy for ailments such as stroke, thrombosis and atherosclerosis.
Prior to joining the Lehigh faculty, Zhang served as a Postdoctoral Fellow in Biophysics at Harvard Medical School and as Principal Investigator at the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. His work has been published in journals such as Science, Nature, and PNAS, and he has presented at conferences around the world. He is a member of the American Heart Association, the American Society for Biochemistry and Molecular Biology, the Biophysical Society, the American Physiological Society, the Society for Experimental Biology and Medicine, and Sigma Xi.