Predicting First Traversal Times for Virions and Nanoparticles in Mucus with Slowed Diffusion

Abstract

Particle-tracking experiments focusing on virions or nanoparticles in mucus have measured mean-square displacements and reported diffusion coefficients that are orders of magnitude smaller than the diffusion coefficients of such particles in water. Accurate description of this subdiffusion is important to properly estimate the likelihood of virions traversing the mucus boundary layer and infecting cells in the epithelium. However, there are several candidate models for diffusion that can fit experimental measurements of mean-square displacements. We show that these models yield very different estimates for the time taken for subdiffusive virions to traverse through a mucus layer. We explain why fits of subdiffusive mean-square displacements to standard diffusion models may be misleading. Relevant to human immunodeficiency virus infection, using computational methods for fractional subdiffusion, we show that subdiffusion in normal acidic mucus provides a more effective barrier against infection than previously thought. By contrast, the neutralization of the mucus by alkaline semen, after sexual intercourse, allows virions to cross the mucus layer and reach the epithelium in a short timeframe. The computed barrier protection from fractional subdiffusion is some orders of magnitude greater than that derived by fitting standard models of diffusion to subdiffusive data.

Thermodynamic equilibrium dose-response models for MERS-CoV infection reveal a potential protective role of human lung mucus but not for SARS-CoV-2

“…This is accommodated in the F v term, which is determined by both K mucin and the mucin concentration according to Equation 8 . To develop the model it may be possible to apply the fate and transport approaches developed by Weir and Haas (2011) to viruses using the K mucin and mucin concentrations and also other diffusion approaches such as that developed for viruses moving through mucus ( Erickson et al. 2015 ).…”

How virus size and attachment parameters affect the temperature sensitivity of virus binding to host cells: Predictions of a thermodynamic model for arboviruses and HIV

“…The temperature dependence of virus diffusion in mucus (Erickson et al 2015) could also be considered not only in mechanistic dose-response models for viral infection at mucosal epithelial membranes in the intestine (Gale 2018) but also in terms of therapeutics when combined with the thermodynamic approach developed here. Normal, acidic cervicovaginal mucus greatly hinders the movement of virions of HSV and HIV, whereas mucus that is neutralized by semen provides a much less effective barrier against the same virions (Erickson et al 2015). Thus binding of the HSV or HIV virion to a ZnOT particle may not only decrease its diffusion coefficient in mucus but also make the magnitude of ΔS a_immob more negative hence reducing the binding affinity of those virions which do make it through the mucus to the epithelial cell surface at human body temperature.…”

The particle in the spider's web: transport through biological hydrogels

“…81–84 Subdiffusion refers to diffusion behavior in which the mean squared displacement of individual particles scales with t α for α <1, rather than with t 1 as in standard diffusion; subdiffusion or transient subdiffusion is commonly observed in gel transport studies and can impact important parameters such as passage time through a gel. 85,86 …”