Richard Reeve

Predicting the public health benefit of vaccinating cattle against Escherichia coli O157

Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global pathogen is Escherichia coli O157, which causes a serious and sometimes fatal gastrointestinal illness. Cattle are the main reservoir for E. coli O157, and vaccines for cattle now exist. However, adoption of vaccines is being delayed by conflicting responsibilities of veterinary and public health agencies, economic drivers, and because clinical trials cannot easily test interventions across species boundaries, lack of information on the public health benefits. Here, we examine transmission risk across the cattle–human species boundary and show three key results. First, supershedding of the pathogen by cattle is associated with the genetic marker stx2. Second, by quantifying the link between shedding density in cattle and human risk, we show that only the relatively rare supershedding events contribute significantly to human risk. Third, we show that this finding has profound consequences for the public health benefits of the cattle vaccine. A naïve evaluation based on efficacy in cattle would suggest a 50% reduction in risk; however, because the vaccine targets the major source of human risk, we predict a reduction in human cases of nearly 85%. By accounting for nonlinearities in transmission across the human–animal interface, we show that adoption of these vaccines by the livestock industry could prevent substantial numbers of human E. coli O157 cases.

Talking to Godot: dialogue with a mobile robot

Godot is a mobile robot platform that serves as a testbed for the interface between a sophisticated low-level robot navigation and a symbolic high-level spoken dialogue system. The interesting feature of this combined system is that information flows in two directions: (1) the navigation system. supplies landmark; information from the cognitive map used for the interpretation of the users utterances in the dialogue system; and (2) the semantic content of utterances analysed by the dialogue system are used to adjust probabilities about the robots position in the navigation system.

Robot phonotaxis in the wild : a biologically inspired approach to outdoor sound localization

Cricket phonotaxis (sound localization behavior) was implemented on an autonomous outdoor robot platform inspired by cockroach locomotion. This required the integration of a novel robot morphology (Whegs) with a biologically based auditory processing circuit and neural control system, as well as interfacing this to a new tracking device and software architecture for running robot experiments. In repeated tests, the robot is shown to be capable of tracking towards a simulated male cricket song over natural terrain. Range fractionation and gain control were added to the auditory control circuit in order to deal with the substantial change in amplitude of the signal as the robot approached the outdoor sound stimulus. We also discuss issues related to acoustic interference from motor noise, the need for a motor feedback mechanism to better regulate the drive signal and plans for future work incorporating additional sensory systems on this platform.

New neural circuits for robot phonotaxis

W. Grey Walter built robotic systems to improve understanding of biological systems. In that tradition, this paper reports ongoing work on a robot model of cricket sound localization. The main advances are the inclusion of a much larger range of neuroethological detail, and the investigation of multimodal influences on the behaviour. The former allows exploration of the functionality of identified neurons in the insect, including the possible roles of multiple sensory fibres, mutually inhibitory connections, and brain neurons with pattern-filtering properties. The latter focuses on the inclusion of an optomotor stabilization response, and how this might improve tracking, particularly under conditions of random disturbance.

Sequence-based prediction for vaccine strain selection and identification of antigenic variability in Foot-and-Mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence – by controlling for phylogenetic structure – for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease.

An ecological approach to assessing the epidemiology of antimicrobial resistance in animal and human populations

We examined long-term surveillance data on antimicrobial resistance (AMR) in Salmonella Typhimurium DT104 (DT104) isolates from concurrently sampled and sympatric human and animal populations in Scotland. Using novel ecological and epidemiological approaches to examine diversity, and phenotypic and temporal relatedness of the resistance profiles, we assessed the more probable source of resistance of these two populations. The ecological diversity of AMR phenotypes was significantly greater in human isolates than in animal isolates, at the resolution of both sample and population. Of 5200 isolates, there were 65 resistance phenotypes, 13 unique to animals, 30 unique to humans and 22 were common to both. Of these 22, 11 were identified first in the human isolates, whereas only five were identified first in the animal isolates. We conclude that, while ecologically connected, animals and humans have distinguishable DT104 communities, differing in prevalence, linkage and diversity. Furthermore, we infer that the sympatric animal population is unlikely to be the major source of resistance diversity for humans. This suggests that current policy emphasis on restricting antimicrobial use in domestic animals may be overly simplistic. While these conclusions pertain to DT104 in Scotland, this approach could be applied to AMR in other bacteria–host ecosystems.

New technologies for testing a model of cricket phonotaxis on an outdoor robot

If biological inspiration can be used to build robots that deal robustly with complex environments, it should be possible to demonstrate that ‘biorobots’ can function in natural environments. We report on initial outdoor experiments with a robot designed to emulate cricket behaviour. The work integrates a detailed neural model of auditory localisation in the cricket with a robot morphology that incorporates principles of six-legged locomotion. We demonstrate that it can successfully track a cricket calling song over natural terrain. Limitations in its capability are evaluated, and a number of biologically based improvements are suggested for future work.

An analysis of neural models for walking control

A large space of different neural models exists from simple mathematical abstractions to detailed biophysical representations with strongly differing levels of complexity and biological relevance. Previous comparisons between models have looked at biological realism or mathematical tractability rather than expressive power. This paper, however, investigates whether more sophisticated models are better suited to a complex sensorimotor control task than simpler ones, or whether the more general nature of groups of the simpler neurons allows them to collectively solve complex tasks better despite their individual simplicity. Many models have been proposed or used for sensorimotor control tasks such as the control of locomotion. Four such neural models with varying levels of complexity were chosen. Controllers made of networks of each neural type were evolved to generate locomotion in a simulated dynamically stable four-legged robot using a genetic algorithm. The problem domain was chosen as one for which no simple solution could be hand crafted and which, with its tight sensorimotor coupling, had strongly time-dependent properties as is common in many biological control tasks. Analysis of the results shows that the most complex and biologically based model is significantly better at walking control, even producing recognizable gaits.

Reafferent or Redundant: Integration of Phonotaxis and Optomotor Behavior in Crickets and Robots:

A general problem in understanding the mechanisms underlying animal behavior is the integration or interaction of different sensorimotor systems. Webb and Harrison (2000a, b) investigated the addition of an optomotor reflex to a sound-localizing robot modeled on cricket behavior. Böhm, Schildberger, and Huber (1991) proposed a simple additive mechanism to explain how the cricket combines the two behaviors. Problems implementing this on the robot led us to propose an alternative inhibition mechanism, which proved effective. Here we directly compare these two possibilities and several further alternatives. First, in a simulation of the open-loop paradigm used by Böhm et al. we demonstrate that there are at least five algorithms (including “efferent copy”) that may adequately account for the data they present. We then consider possible neural implementations of several of these schemes, and test them in robot experiments. The results suggest that inhibition is both neurally plausible and effective as a means of combining these behaviors in real sensorimotor situations.

Exploiting strain diversity to expose transmission heterogeneities and predict the impact of targeting supershedding

When a few individuals generate disproportionately many secondary cases, targeted interventions can theoretically lead to highly efficient control of the spread of infection. Practical exploitation of heterogeneous transmission requires the sources of variability to be quantified, yet it is unusual to have empirical data of sufficient resolution to distinguish their effects. Here, we exploit extensive data on pathogen shedding densities and the distribution of cases, collected from the same population within the same spatio-temporal window, to expose the comparative epidemiology of independent Escherichia coli O157 strains. For this zoonotic pathogen, which exhibits high-density shedding (supershedding) and heterogeneous transmission in its cattle reservoir, whether targeting supershedding could be an effective control depends critically on the proposed link between shedding density and transmissibility. We substantiate this link by showing that our supershedder strain has nearly triple the R(0) of our non-supershedder strain. We show that observed transmission heterogeneities are strongly driven by superspreading in addition to supershedding, but that for the supershedder strain, the dominant strain in our study population, there remains sufficient heterogeneity in contribution to R(0) from different shedding densities to allow exploitation for control. However, in the presence of substantial within-host variability, our results indicate that rather than seek out supershedders themselves, the most effective controls would directly target the phenomenon of pathogen supershedding with the aim of interrupting or preventing high shedding densities. In this system, multiple sources of heterogeneity have masked the role of shedding densities-our potential targets for control. This analysis demonstrates the critical importance of disentangling the effects of multiple sources of heterogeneity when designing targeted interventions.