David Schley

Relationship Between Clinical Signs and Transmission of an Infectious Disease and the Implications for Control

Livestock experiments provide precise parameters for incubation and infectious periods for foot-and-mouth disease virus. Control of many infectious diseases relies on the detection of clinical cases and the isolation, removal, or treatment of cases and their contacts. The success of such “reactive” strategies is influenced by the fraction of transmission occurring before signs appear. We performed experimental studies of foot-and-mouth disease transmission in cattle and estimated this fraction at less than half the value expected from detecting virus in body fluids, the standard proxy measure of infectiousness. This is because the infectious period is shorter (mean 1.7 days) than currently realized, and animals are not infectious until, on average, 0.5 days after clinical signs appear. These results imply that controversial preemptive control measures may be unnecessary; instead, efforts should be directed at early detection of infection and rapid intervention.

Quantifying the Risk of Localised Animal Movement Bans for Foot-and-Mouth Disease

The maintenance of disease-free status from Foot-and-Mouth Disease is of significant socio-economic importance to countries such as the UK. The imposition of bans on the movement of susceptible livestock following the discovery of an outbreak is deemed necessary to prevent the spread of what is a highly contagious disease, but has a significant economic impact on the agricultural community in itself. Here we consider the risk of applying movement restrictions only in localised zones around outbreaks in order to help evaluate how quickly nation-wide restrictions could be lifted after notification. We show, with reference to the 2001 and 2007 UK outbreaks, that it would be practical to implement such a policy provided the basic reproduction ratio of known infected premises can be estimated. It is ultimately up to policy makers and stakeholders to determine the acceptable level of risk, involving a cost benefit analysis of the potential outcomes, but quantifying the risk of spread from different sized zones is a prerequisite for this. The approach outlined is relevant to the determination of control zones and vaccination policies and has the potential to be applied to future outbreaks of other diseases.

Arenavirus budding resulting from viral-protein-associated cell membrane curvature

Viral replication occurs within cells, with release (and onward infection) primarily achieved through two alternative mechanisms: lysis, in which virions emerge as the infected cell dies and bursts open; or budding, in which virions emerge gradually from a still living cell by appropriating a small part of the cell membrane. Virus budding is a poorly understood process that challenges current models of vesicle formation. Here, a plausible mechanism for arenavirus budding is presented, building on recent evidence that viral proteins embed in the inner lipid layer of the cell membrane. Experimental results confirm that viral protein is associated with increased membrane curvature, whereas a mathematical model is used to show that localized increases in curvature alone are sufficient to generate viral buds. The magnitude of the protein-induced curvature is calculated from the size of the amphipathic region hypothetically removed from the inner membrane as a result of translation, with a change in membrane stiffness estimated from observed differences in virion deformation as a result of protein depletion. Numerical results are based on experimental data and estimates for three arenaviruses, but the mechanisms described are more broadly applicable. The hypothesized mechanism is shown to be sufficient to generate spontaneous budding that matches well both qualitatively and quantitatively with experimental observations.

Within-group contact of cattle in dairy barns and the implications for disease transmission.

The prevention, control and reduction of livestock diseases require a good understanding of how the underlying causative agents are transmitted. On livestock premises the rate of spread is strongly determined by the contact, both direct and indirect, between infectious and susceptible individuals. Here we consider contact amongst barn-housed dairy cattle, one of the most important UK livestock sectors. A novel observational study of faecal spread indicates that the level of contact an individual animal can have with other herd members via this transmission pathway is very high (80 ± 4% within sub-units). Additional observational studies indicate the possible level of direct physical contact an animal has with other group members (an approximate Poisson distribution with a mean rate of 14.4 distinct individuals per hour), and the potential for indirect transfer via inanimate objects by considering the proportion of the herd that touched a given gatepost in the milking parlour each day (43 ± 6%). Results suggest that mixing may be considered homogeneous for certain pathogens, but that the spread of diseases transmitted along only specific routes requires the incorporation of within group contact structures.

Direct Observation of Membrane Insertion by Enveloped Virus Matrix Proteins by Phosphate Displacement

Enveloped virus release is driven by poorly understood proteins that are functional analogs of the coat protein assemblies that mediate intracellular vesicle trafficking. We used differential electron density mapping to detect membrane integration by membrane-bending proteins from five virus families. This demonstrates that virus matrix proteins replace an unexpectedly large portion of the lipid content of the inner membrane face, a generalized feature likely to play a role in reshaping cellular membranes.

Modelling the influence of foot-and-mouth disease vaccine antigen stability and dose on the bovine immune response

Foot and mouth disease virus causes a livestock disease of significant global socio-economic importance. Advances in its control and eradication depend critically on improvements in vaccine efficacy, which can be best achieved by better understanding the complex within-host immunodynamic response to inoculation. We present a detailed and empirically parametrised dynamical mathematical model of the hypothesised immune response in cattle, and explore its behaviour with reference to a variety of experimental observations relating to foot and mouth immunology. The model system is able to qualitatively account for the observed responses during in-vivo experiments, and we use it to gain insight into the incompletely understood effect of single and repeat inoculations of differing dosage using vaccine formulations of different structural stability.

Modelling Foot-and-Mouth Disease Virus Dynamics in Oral Epithelium to Help Identify the Determinants of Lysis

Foot-and-mouth disease virus (FMDV) causes an economically important disease of cloven-hoofed livestock; of interest here is the difference in lytic behaviour that is observed in bovine epithelium. On the skin around the feet and tongue, the virus rapidly replicates, killing cells, and resulting in growing lesions, before eventually being cleared by the immune response. In contrast, there is usually minimal lysis in the soft palate, but virus may persist in tissue long after the animal has recovered from the disease. Persistence of virus has important implications for disease control, while identifying the determinant of lysis in epithelium is potentially important for the development of prophylactics. To help identify which of the differences between oral and pharyngeal epithelium are responsible for such dramatically divergent FMDV dynamics, a simple model has been developed, in which virus concentration is made explicit to allow the lytic behaviour of cells to be fully considered. Results suggest that localised structuring of what are fundamentally similar cells can induce a bifurcation in the behaviour of the system, explicitly whether infection can be sustained or results in mutual extinction, although parameter estimates indicate that more complex factors may be involved in maintaining viral persistence, or that there are as yet unquantified differences between the intrinsic properties of cells in these regions.

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

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.

Foot-and-Mouth Disease Virus, Epithelial Cell Death and PDE Models.

Foot-and-mouth disease virus (FMDV) is a highly infectious anima lvirus that affects cloven-hoofed animals (including cattle, sheep and pigs).Because FMDV is a serious global socio-economic threat, it has been studied extensively for many decades. However, there are still several significant knowledge gaps in the pathogenesis of the disease. In particular, the predilection for certain epithelial tissues to develop vesicular lesions is currently unexplained. For example, epithelial cell lysis is extensive in the epithelial tissue of the bovine tongue, which results in the development of vesicular lesions. Nevertheless, the epithelium of the dorsal soft palate(DSP) does not show similar signs, even though it is a primary infectionsite of FMDV. The factors which inuence epithelial cell death and the development of lesions are the focus of this work, which is one of the few modelling studies on the within-host dynamics of FMDV.With the aim of identifying potential determinants of FMDV-induced epithelial cell lysis in cattle, a spatially explicit 1D PDE model was de-veloped to investigate the roles played by bovine epithelial thickness and cell layer structures. Numerical investigations demonstrated that these two factors alone do not explain the formation of lesions and, consequently,additional biological complexity is essential to explain the bifurcation inepithelial cell behaviour. Detailed exploration of parameter space offered an insight on the importance of potential differences in viral replication and receptor distribution between epithelia and between epithelial cell layers.The 1D epithelial tissue model has been subsequently expanded to a 3D structure, to facilitate the study of the size, as well as the occurrence of lesions, while greater biological realism has been added to the model byincorporating the antiviral activity of interferon to allow its eects on theFMDV dynamics in epithelium to be explored.

A Hypothesised Mechanism for Viral Budding, Supported by Integration of New Protein Associated Curvature Data into a Mathematical Model of the Cell Membrane

Following replication within cells, new virus particles may be released either upon cell death or gradually, by budding out of the surface of still living cells. To develop treatments that can inhibit or interrupt this process requires a better understanding of how it occurs. Here the hypothesis that for certain viruses budding may driven by viral-protein associated curvature of the cell membrane is supported by the application of a mechanistic mathematical model of the membrane. We show that localised increases in curvature alone are sufficient to generate viral buds, while locally induced increases in stiffness accelerate the process and results in tighter buds. Numerical results show good qualitative and quantitative agreement in bud shape and size with experimental observations for arenavirus, for which recent experimental results have confirmed that viral protein is associated with increased membrane curvature.