Researchers discover the biomechanics of Ebola virus attachment to its host cell

It has recently been reported that the number of Ebola cases in the Democratic Republic of the Congo exceeds 1,000, making it the second most serious epidemic of all time after that of West Africa in 2014, during which 29,000 people were infected and more than 11,000 died. This last step is a stark reminder of the urgent need to develop effective prevention and treatment agents for this often fatal disease.

People infected with Ebola are severely affected, including haemorrhagic fever, which can lead to internal bleeding. According to the US Centers for Disease Control and Prevention (CDC), there is currently no specific medical treatment for Ebola.

To develop treatments against the disease, it is essential to understand the mechanisms of the infectious process. Scientists know that to penetrate a human cell, Ebola takes advantage of a natural process called macropinocytosis, whereby the cell "cleans" its environment by internalizing the dead cell debris that surrounds it. Proteins on the cell surface act as receptors, allowing immune cells to recognize dead cell debris and internalize it. The virus interacts with these proteins, called T cell immunoglobulin and mucin domain (TIM) proteins, and uses them to sneak into the cell. Once inside, the membrane of the Ebola virus merges with the endosome that has formed around it and releases its genetic content into the cell.

"Viral RNA further diverts the cellular mechanism for making proteins and replicates within, then they break off the membrane to form a new virus while the healthy host cell dies", says Frank Zhang, an badociate professor of bioengineering and mechanical engineering at Lehigh University.

"It has been shown that the attachment of Ebola host cells to the molecular biomechanics of the interaction between receptors on the surface of the cell and the outer layer of the virus, but the essential quantitative understanding to guide the development of therapies has not yet been developed, "he adds. Anand Jagota, founding chairman of Lehigh's bioengineering department and professor of chemical and biomolecular engineering.

Zhang and Jagota have teamed up to try to better understand the biomechanics of host cell adhesion to the Ebola virus. The project combines Jagota's expertise in the mechanics of computational molecular adhesion with Zhang's focus on mechano-sensing, or the way cells detect and respond to mechanical stimuli. The duo, in collaboration with colleagues Sven Moller-Tank and Wendy Maury of the University of Iowa, has developed a simple model characterizing the biomechanics of host cell adhesion to the Ebola virus. The findings could provide new and useful information on the way to developing effective Ebola treatment. They published their findings in Scientific reports in an article entitled: "Biomechanical Characterization of Host Adhesion to Ebola Virus Induced by TIM Protein".

"We used monomolecular force spectroscopy to quantify the specific interaction forces between TIM proteins of a host cell and Ebola-like particles," Zhang explains.

In addition to shedding light on the important biomechanical parameters for Ebola virus binding to a host cell, the team has also experimentally demonstrated that interactions between TIM virus and Ebola are mechanically comparable to adhesion molecule interactions (by example, selectin). By a simple mechanical model, they further demonstrate how the molecular binding parameters determine whether they are sufficient for viral adhesion.

The model aims to show how it is possible to combine measurements of individual molecules with other physical properties of the system, such as ligand-receptor pair density and membrane stiffness, to predict if and in what way measuring a viral particle will adhere to the cell. membrane. The team models attachment as being determined by adhesion between TIM proteins and phosphatidylserine on the surface of the virus (believed to mediate virus-host attachment) and membrane flexion.

"The simplicity of the model allowed us to highlight the importance of two groups of dimensionless parameters and their potential ability to block adhesion," Jagota said.

Zhang uses single molecule force spectroscopy to monitor, manipulate and measure mechanical forces. For example, in the study, Zhang was bringing a virus-like particle to a cell with its expressed TIM receptor, observing their interaction and separating them to determine the mechanical strength of the interaction or the amount of force required for shoot them. a part.

Jagota uses mathematical models to understand the interaction between Ebola and the cell, which properties represent the Ebola virus – its rigidity, its shape – and what properties represent the cell – the components that it has on its surface – in this interaction.

"The hope is that this quantitative knowledge on the biomechanics of adhesion can be used to predict the conditions of attachment to Ebola," Jagota said. "The long-term goal is that this information contributes to the definition of new pharmacological targets and helps in the development of antiviral treatments essential for the prevention and treatment of Ebola."

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More information:
Matthew A. Dragovich et al., Biomechanical Characterization of Host Adhesion to TIM-induced Ebola Virus, Scientific reports (2019). DOI: 10.1038 / s41598-018-36449-2