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Cell-free transmission of human adenovirus by passive mass transfer in cell culture simulated in a computer model


Yakimovich, A; Gumpert, H; Burckhardt, C J; Lutschg, V A; Jurgeit, A; Sbalzarini, I F; Greber, U F (2012). Cell-free transmission of human adenovirus by passive mass transfer in cell culture simulated in a computer model. Journal of Virology, 86(18):10123-10137.

Abstract

Viruses spread between cells, tissues, and organisms by cell-free and cell-cell transmissions. Both mechanisms enhance disease development, but it is difficult to distinguish between them. Here, we analyzed the transmission mode of human adenovirus (HAdV) in monolayers of epithelial cells by wet laboratory experimentation and a computer simulation. Using live-cell fluorescence microscopy and replication-competent HAdV2 expressing green fluorescent protein, we found that the spread of infection invariably occurred after cell lysis. It was affected by convection and blocked by neutralizing antibodies but was independent of second-round infections. If cells were overlaid with agarose, convection was blocked and round plaques developed around lytic infected cells. Infected cells that did not lyse did not give rise to plaques, highlighting the importance of cell-free transmission. Key parameters for cell-free virus transmission were the time from infection to lysis, the dose of free viruses determining infection probability, and the diffusion of single HAdV particles in aqueous medium. With these parameters, we developed an in silico model using multiscale hybrid dynamics, cellular automata, and particle strength exchange. This so-called white box model is based on experimentally determined parameters and reproduces viral infection spreading as a function of the local concentration of free viruses. These analyses imply that the extent of lytic infections can be determined by either direct plaque assays or can be predicted by calculations of virus diffusion constants and modeling.

Viruses spread between cells, tissues, and organisms by cell-free and cell-cell transmissions. Both mechanisms enhance disease development, but it is difficult to distinguish between them. Here, we analyzed the transmission mode of human adenovirus (HAdV) in monolayers of epithelial cells by wet laboratory experimentation and a computer simulation. Using live-cell fluorescence microscopy and replication-competent HAdV2 expressing green fluorescent protein, we found that the spread of infection invariably occurred after cell lysis. It was affected by convection and blocked by neutralizing antibodies but was independent of second-round infections. If cells were overlaid with agarose, convection was blocked and round plaques developed around lytic infected cells. Infected cells that did not lyse did not give rise to plaques, highlighting the importance of cell-free transmission. Key parameters for cell-free virus transmission were the time from infection to lysis, the dose of free viruses determining infection probability, and the diffusion of single HAdV particles in aqueous medium. With these parameters, we developed an in silico model using multiscale hybrid dynamics, cellular automata, and particle strength exchange. This so-called white box model is based on experimentally determined parameters and reproduces viral infection spreading as a function of the local concentration of free viruses. These analyses imply that the extent of lytic infections can be determined by either direct plaque assays or can be predicted by calculations of virus diffusion constants and modeling.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Special Collections > SystemsX.ch
Special Collections > SystemsX.ch > Research, Technology and Development Projects > InfectX
Special Collections > SystemsX.ch > Research, Technology and Development Projects > LipidX
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:cell lysis; multi-scale model; computational simulation; infection spreading, virus transmission
Language:English
Date:11 July 2012
Deposited On:13 Sep 2012 12:18
Last Modified:05 Apr 2016 15:57
Publisher:American Society for Microbiology
ISSN:0022-538X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1128/JVI.01102-12
PubMed ID:22787215
Permanent URL: http://doi.org/10.5167/uzh-64610

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