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Using Mathematical Modelling to Explore Hypotheses about the Role of Bovine Epithelium Structure in Foot-And-Mouth Disease Virus-Induced Cell Lysis.

Giorgakoudi K, Gubbins S, Ward J, Juleff N, Zhang Z, Schley D - PLoS ONE (2015)

Bottom Line: By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate).The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally.However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates.

View Article: PubMed Central - PubMed

Affiliation: The Pirbright Institute, Pirbright, Surrey, United Kingdom; Department of Mathematical Sciences, Loughborough University, Loughborough, Leicestershire, United Kingdom.

ABSTRACT
Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals. FMD virus (FMDV) shows a strong tropism for epithelial cells, and FMD is characterised by cell lysis and the development of vesicular lesions in certain epithelial tissues (for example, the tongue). By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate). The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally. In order to identify the factors which drive cell lysis, and consequently determine the development of lesions, we developed a partial differential equation model of FMDV infection in bovine epithelial tissues and used it to explore a range of hypotheses about epithelium structure which could be driving differences in lytic behaviour observed in different tissues. Our results demonstrate that, based on current parameter estimates, epithelial tissue thickness and cell layer structure are unlikely to be determinants of FMDV-induced cell lysis. However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates.

No MeSH data available.


Related in: MedlinePlus

Extensive sensitivity analysis.LHS applied to the model with tested parameters ranging from 0.1 to 10 times their estimated values shows the consistency of results in predicting destruction of the cellular column. As parameters are varied, Sc in graph (a) of the DSP remains bounded below 1 × 10−6 and VcSc in graph (c) below 4 × 10−7 PFU/cm, apart from at surface where Sc < 6 × 10−6 and VcSc < 15 × 10−7 PFU/cm. In graph (b) of the tongue, Sc is bounded below 10−5 for most of the tissue, but closer to the granular layer Sc < 3 × 10−3. Similarly, in graph (d) VcSc is bounded below 10−5 PFU/cm for most of the tissue, but closer to the granular layer VcSc < 5 × 10−4 PFU/cm. The range of possible results is plotted in 5 percentile steps (shaded), from 100 replicates. Parameters tested: K1/2, μ, DV, QV, V0, m1, m2, m3.
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pone.0138571.g005: Extensive sensitivity analysis.LHS applied to the model with tested parameters ranging from 0.1 to 10 times their estimated values shows the consistency of results in predicting destruction of the cellular column. As parameters are varied, Sc in graph (a) of the DSP remains bounded below 1 × 10−6 and VcSc in graph (c) below 4 × 10−7 PFU/cm, apart from at surface where Sc < 6 × 10−6 and VcSc < 15 × 10−7 PFU/cm. In graph (b) of the tongue, Sc is bounded below 10−5 for most of the tissue, but closer to the granular layer Sc < 3 × 10−3. Similarly, in graph (d) VcSc is bounded below 10−5 PFU/cm for most of the tissue, but closer to the granular layer VcSc < 5 × 10−4 PFU/cm. The range of possible results is plotted in 5 percentile steps (shaded), from 100 replicates. Parameters tested: K1/2, μ, DV, QV, V0, m1, m2, m3.

Mentions: In Fig 5 results of the LHS sensitivity analysis for the default viral entry points for DSP and tongue are presented. Because the model is highly sensitive to parameters ξ and ρ, these are excluded from this investigation, but their effect on the model is explored more extensively in the next section. Parameters explored here are K1/2, μ, DV, QV and V0 for which tested values range from 0.1 × to 10 × their default estimates, and m1, m2, and m3 which take values from the range [1, 100]. Results presented in Fig 5 are consistent with the findings of the model for the original parameter values, predicting cell death of the entire epithelial cell column. Other viral entry points produce similar results.


Using Mathematical Modelling to Explore Hypotheses about the Role of Bovine Epithelium Structure in Foot-And-Mouth Disease Virus-Induced Cell Lysis.

Giorgakoudi K, Gubbins S, Ward J, Juleff N, Zhang Z, Schley D - PLoS ONE (2015)

Extensive sensitivity analysis.LHS applied to the model with tested parameters ranging from 0.1 to 10 times their estimated values shows the consistency of results in predicting destruction of the cellular column. As parameters are varied, Sc in graph (a) of the DSP remains bounded below 1 × 10−6 and VcSc in graph (c) below 4 × 10−7 PFU/cm, apart from at surface where Sc < 6 × 10−6 and VcSc < 15 × 10−7 PFU/cm. In graph (b) of the tongue, Sc is bounded below 10−5 for most of the tissue, but closer to the granular layer Sc < 3 × 10−3. Similarly, in graph (d) VcSc is bounded below 10−5 PFU/cm for most of the tissue, but closer to the granular layer VcSc < 5 × 10−4 PFU/cm. The range of possible results is plotted in 5 percentile steps (shaded), from 100 replicates. Parameters tested: K1/2, μ, DV, QV, V0, m1, m2, m3.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4592007&req=5

pone.0138571.g005: Extensive sensitivity analysis.LHS applied to the model with tested parameters ranging from 0.1 to 10 times their estimated values shows the consistency of results in predicting destruction of the cellular column. As parameters are varied, Sc in graph (a) of the DSP remains bounded below 1 × 10−6 and VcSc in graph (c) below 4 × 10−7 PFU/cm, apart from at surface where Sc < 6 × 10−6 and VcSc < 15 × 10−7 PFU/cm. In graph (b) of the tongue, Sc is bounded below 10−5 for most of the tissue, but closer to the granular layer Sc < 3 × 10−3. Similarly, in graph (d) VcSc is bounded below 10−5 PFU/cm for most of the tissue, but closer to the granular layer VcSc < 5 × 10−4 PFU/cm. The range of possible results is plotted in 5 percentile steps (shaded), from 100 replicates. Parameters tested: K1/2, μ, DV, QV, V0, m1, m2, m3.
Mentions: In Fig 5 results of the LHS sensitivity analysis for the default viral entry points for DSP and tongue are presented. Because the model is highly sensitive to parameters ξ and ρ, these are excluded from this investigation, but their effect on the model is explored more extensively in the next section. Parameters explored here are K1/2, μ, DV, QV and V0 for which tested values range from 0.1 × to 10 × their default estimates, and m1, m2, and m3 which take values from the range [1, 100]. Results presented in Fig 5 are consistent with the findings of the model for the original parameter values, predicting cell death of the entire epithelial cell column. Other viral entry points produce similar results.

Bottom Line: By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate).The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally.However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates.

View Article: PubMed Central - PubMed

Affiliation: The Pirbright Institute, Pirbright, Surrey, United Kingdom; Department of Mathematical Sciences, Loughborough University, Loughborough, Leicestershire, United Kingdom.

ABSTRACT
Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals. FMD virus (FMDV) shows a strong tropism for epithelial cells, and FMD is characterised by cell lysis and the development of vesicular lesions in certain epithelial tissues (for example, the tongue). By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate). The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally. In order to identify the factors which drive cell lysis, and consequently determine the development of lesions, we developed a partial differential equation model of FMDV infection in bovine epithelial tissues and used it to explore a range of hypotheses about epithelium structure which could be driving differences in lytic behaviour observed in different tissues. Our results demonstrate that, based on current parameter estimates, epithelial tissue thickness and cell layer structure are unlikely to be determinants of FMDV-induced cell lysis. However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates.

No MeSH data available.


Related in: MedlinePlus