Disrupted seasonal biology impacts health, food security and ecosystems.

The rhythm of life on earth is shaped by seasonal changes in the environment. Plants and animals show profound annual cycles in physiology, health, morphology, behaviour and demography in response to environmental cues. Seasonal biology impacts ecosystems and agriculture, with consequences for humans and biodiversity. Human populations show robust annual rhythms in health and well-being, and the birth month can have lasting effects that persist throughout life. This review emphasizes the need for a better understanding of seasonal biology against the backdrop of its rapidly progressing disruption through climate change, human lifestyles and other anthropogenic impact. Climate change is modifying annual rhythms to which numerous organisms have adapted, with potential consequences for industries relating to health, ecosystems and food security. Disconcertingly, human lifestyles under artificial conditions of eternal summer provide the most extreme example for disconnect from natural seasons, making humans vulnerable to increased morbidity and mortality. In this review, we introduce scenarios of seasonal disruption, highlight key aspects of seasonal biology and summarize from biomedical, anthropological, veterinary, agricultural and environmental perspectives the recent evidence for seasonal desynchronization between environmental factors and internal rhythms. Because annual rhythms are pervasive across biological systems, they provide a common framework for trans-disciplinary research.

Low-coverage vaccination strategies for the conservation of endangered species.

The conventional objective of vaccination programmes is to eliminate infection by reducing the reproduction number of an infectious agent to less than one, which generally requires vaccination of the majority of individuals. In populations of endangered wildlife, the intervention required to deliver such coverage can be undesirable and impractical; however, endangered populations are increasingly threatened by outbreaks of infectious disease for which effective vaccines exist. As an alternative, wildlife epidemiologists could adopt a vaccination strategy that protects a population from the consequences of only the largest outbreaks of disease. Here we provide a successful example of this strategy in the Ethiopian wolf, the world's rarest canid, which persists in small subpopulations threatened by repeated outbreaks of rabies introduced by domestic dogs. On the basis of data from past outbreaks, we propose an approach that controls the spread of disease through habitat corridors between subpopulations and that requires only low vaccination coverage. This approach reduces the extent of rabies outbreaks and should significantly enhance the long-term persistence of the population. Our study shows that vaccination used to enhance metapopulation persistence through elimination of the largest outbreaks of disease requires lower coverage than the conventional objective of reducing the reproduction number of an infectious agent to less than one.

From phenotype to genotype: a Bayesian solution.

The study of biological systems commonly depends on inferring the state of a 'hidden' variable, such as an underlying genotype, from that of an 'observed' variable, such as an expressed phenotype. However, this cannot be achieved using traditional quantitative methods when more than one genetic mechanism exists for a single observable phenotype. Using a novel latent class Bayesian model, it is possible to infer the prevalence of different genetic elements in a population given a sample of phenotypes. As an exemplar, data comprising phenotypic resistance to six antimicrobials obtained from passive surveillance of Salmonella Typhimurium DT104 are analysed to infer the prevalence of individual resistance genes, as well as the prevalence of a genomic island known as SGI1 and its variants. Three competing models are fitted to the data and distinguished between using posterior predictive p-values to assess their ability to predict the observed number of unique phenotypes. The results suggest that several SGI1 variants circulate in a few fixed forms through the population from which our data were derived. The methods presented could be applied to other types of phenotypic data, and represent a useful and generic mechanism of inferring the genetic population structure of organisms.

Critical interplay between parasite differentiation, host immunity, and antigenic variation in trypanosome infections.

Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, we introduce a mechanistic framework for modeling within-host infection dynamics. Our analysis focuses first on a single parasitemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. A major feature of trypanosome infections is the interaction between variant-specific host immunity and density-dependent parasite differentiation to transmission life stages. In this study, we investigate how the interplay between these two types of control depends on the modular structure of the parasite antigenic archive. Our model shows that the degree of synchronization in stochastic variant emergence determines the relative dominance of general over specific control within a single peak. A requirement for multiple-peak dynamics is a critical switch rate between blocks of antigenic variants, which implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics and provides insights into the evolution of trypanosomes.

Population biology of multihost pathogens.

The majority of pathogens, including many of medical and veterinary importance, can infect more than one species of host. Population biology has yet to explain why perceived evolutionary advantages of pathogen specialization are, in practice, outweighed by those of generalization. Factors that predispose pathogens to generalism include high levels of genetic diversity and abundant opportunities for cross-species transmission, and the taxonomic distributions of generalists and specialists appear to reflect these factors. Generalism also has consequences for the evolution of virulence and for pathogen epidemiology, making both much less predictable. The evolutionary advantages and disadvantages of generalism are so finely balanced that even closely related pathogens can have very different host range sizes.

Dynamics of the 2001 UK foot and mouth epidemic: stochastic dispersal in a heterogeneous landscape.

Foot-and-mouth is one of the world's most economically important livestock diseases. We developed an individual farm-based stochastic model of the current UK epidemic. The fine grain of the epidemiological data reveals the infection dynamics at an unusually high spatiotemporal resolution. We show that the spatial distribution, size, and species composition of farms all influence the observed pattern and regional variability of outbreaks. The other key dynamical component is long-tailed stochastic dispersal of infection, combining frequent local movements with occasional long jumps. We assess the history and possible duration of the epidemic, the performance of control strategies, and general implications for disease dynamics in space and time.

Overviews of pathogen emergence: which pathogens emerge, when and why?

An emerging pathogen has been defined as the causative agent of an infectious disease whose incidence is increasing following its appearance in a new host population or whose incidence is increasing in an existing population as a result of long-term changes in its underlying epidemiology (Woolhouse and Dye 2001). Although we appear to be in a period where novel diseases are appearing and old diseases are spreading at an unprecedented rate, disease emergence per se is not a new phenomenon. It is almost certain that disease emergence is a routine event in the evolutionary ecology of pathogens, and part of a ubiquitous response of pathogen populations to shifting arrays of host species. While our knowledge of emerging diseases is, for the most part, limited to the time span of the human lineage, this history provides us with a modern reflection of these deeper evolutionary processes, and it is clear from this record that at many times throughout human history, demographic and behavioural changes in society have provided opportunities for pathogens to emerge.

Molecular characterization of SAT-2 foot-and-mouth disease virus isolates obtained from cattle during a four-month period in 2001 in Limpopo Province, South Africa.

Foot-and-mouth disease (FMD) is an acute, highly contagious viral infection of domestic and wild cloven-hoofed animals. The virus is a single-stranded RNA virus that has a high rate of nucleotide mutation and amino acid substitution. In southern Africa the South African Territories (SAT) 1-3 serotypes of FMD virus are maintained by large numbers of African buffaloes (Syncerus caffer), which provide a potential source of infection for domestic livestock and wild animals. During February 2001, an outbreak of SAT-2 was recorded in cattle in the FMD control zone of South Africa, adjacent to the Kruger National Park (KNP). They had not been vaccinated against the disease since they form the buffer between the vaccination and free zones but in the face of the outbreak, they were vaccinated as part of the control measures to contain the disease. The virus was, however, isolated from some of them on several occasions up to May 2001. These isolates were characterized to determine the rate of genetic change in the main antigenic determinant, the 1 D/2A gene. Nucleotide substitutions at 12 different sites were identified of which five led to amino acid changes. Three of these occurred in known antigenic sites, viz. the GH-loop and C-terminal part of the protein, and two of these have previously been shown to be subject to positive selection. Likelihood models indicated that the ratio of non-synonymous to synonymous changes among the outbreak sequences recovered from cattle was four times higher than among comparable sequences isolated from wildlife, suggesting that the virus may be under greater selective pressure during rapid transmission events.

Molecular epidemiology identifies only a single rabies virus variant circulating in complex carnivore communities of the Serengeti.

Understanding the transmission dynamics of generalist pathogens that infect multiple host species is essential for their effective control. Only by identifying those host populations that are critical to the permanent maintenance of the pathogen, as opposed to populations in which outbreaks are the result of 'spillover' infections, can control measures be appropriately directed. Rabies virus is capable of infecting a wide range of host species, but in many ecosystems, particular variants circulate among only a limited range of potential host populations. The Serengeti ecosystem (in northwestern Tanzania) supports a complex community of wild carnivores that are threatened by generalist pathogens that also circulate in domestic dog populations surrounding the park boundaries. While the combined assemblage of host species appears capable of permanently maintaining rabies in the ecosystem, little is known about the patterns of circulation within and between these host populations. Here we use molecular phylogenetics to test whether distinct virus-host associations occur in this species-rich carnivore community. Our analysis identifies a single major variant belonging to the group of southern Africa canid-associated viruses (Africa 1b) to be circulating within this ecosystem, and no evidence for species-specific grouping. A statistical parsimony analysis of nucleoprotein and glycoprotein gene sequence data is consistent with both within- and between-species transmission events. While likely differential sampling effort between host species precludes a definitive inference, the results are most consistent with dogs comprising the reservoir of rabies and emphasize the importance of applying control efforts in dog populations.

Characterisation of a SAT-1 outbreak of foot-and-mouth disease in captive African buffalo (Syncerus caffer): clinical symptoms, genetic characterisation and phylogenetic comparison of outbreak isolates.

African buffalo (Syncerus caffer) play an important role in the maintenance of the SAT types of foot-and-mouth disease (FMD) in southern Africa. These long-term carriers mostly become sub-clinically infected, maintaining the disease and posing a threat to other susceptible wildlife and domestic species. During an unrelated bovine tuberculosis experiment using captive buffalo in the Kruger National Park (KNP), an outbreak of SAT-1 occurred and was further investigated. The clinical signs were recorded and all animals demonstrated significant weight loss and lymphopenia that lasted 100 days. In addition, the mean cell volume and mean cell haemoglobin values were significantly higher than before the outbreak started. Virus was isolated from several buffalo over a period of 167 days post infection and the molecular clock estimated to be 3 x 10(-5) nucleotide substitutions per site per day. Seven amino acid changes occurred of which four occurred in hypervariable regions previously described for SAT-1. The genetic relationship of the outbreak virus was compared to buffalo viruses previously obtained from the KNP but the phylogeny was largely unresolved, therefore the relationship of this outbreak strain to others isolated from the KNP remains unclear.

One Health contributions towards more effective and equitable approaches to health in low- and middle-income countries.

Emerging zoonoses with pandemic potential are a stated priority for the global health security agenda, but endemic zoonoses also have a major societal impact in low-resource settings. Although many endemic zoonoses can be treated, timely diagnosis and appropriate clinical management of human cases is often challenging. Preventive 'One Health' interventions, e.g. interventions in animal populations that generate human health benefits, may provide a useful approach to overcoming some of these challenges. Effective strategies, such as animal vaccination, already exist for the prevention, control and elimination of many endemic zoonoses, including rabies, and several livestock zoonoses (e.g. brucellosis, leptospirosis, Q fever) that are important causes of human febrile illness and livestock productivity losses in low- and middle-income countries. We make the case that, for these diseases, One Health interventions have the potential to be more effective and generate more equitable benefits for human health and livelihoods, particularly in rural areas, than approaches that rely exclusively on treatment of human cases. We hypothesize that applying One Health interventions to tackle these health challenges will help to build trust, community engagement and cross-sectoral collaboration, which will in turn strengthen the capacity of fragile health systems to respond to the threat of emerging zoonoses and other future health challenges. One Health interventions thus have the potential to align the ongoing needs of disadvantaged communities with the concerns of the broader global community, providing a pragmatic and equitable approach to meeting the global goals for sustainable development and supporting the global health security agenda.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'.

A centuries-long epidemic of scrapie in British sheep?

The apparent persistence of scrapie in British sheep for more than 250 years is difficult to explain. Susceptibility to scrapie is associated with particular alleles at a single locus, the PrP gene. As the only known effect of these alleles is to confer susceptibility to a fatal disease, natural selection is expected to reduce their frequency, as has been observed in practice during scrapie outbreaks in single sheep flocks. Susceptibility alleles, and hence scrapie itself, are therefore expected to become rare, yet the disease remains widespread. We suggest that the paradox of scrapie's persistence can be explained by the exceptionally long time-scales inherent in the epidemiology of the disease. It is proposed that scrapie should be regarded as epidemic in British sheep but, unlike more familiar epidemics, which have time-scales of months or years, the scrapie epidemic has a time-scale of centuries. This interpretation implies that scrapie should eventually disappear from the sheep population.

Evidence for positive selection in foot-and-mouth disease virus capsid genes from field isolates.

The nature of selection on capsid genes of foot-and-mouth disease virus (FMDV) was characterized by examining the ratio of nonsynonymous to synonymous substitutions in 11 data sets of sequences obtained from six different serotypes of FMDV. Using a method of analysis that assigns each codon position to one of a number of estimated values of nonsynonymous to synonymous ratio, significant evidence of positive selection was identified in 5 data sets, operating at 1-7% of codon positions. Evidence of positive selection was identified in complete capsid sequences of serotypes A and C and in VP1 sequences of serotypes SAT 1 and 2. Sequences of serotype SAT-2 recovered from a persistently infected African buffalo also revealed evidence for positive selection. Locations of codons under positive selection coincide closely with those of antigenic sites previously identified with the use of monoclonal antibody escape mutants. The vast majority of codons are under mild to strong purifying selection. However, these results suggest that arising antigenic variants benefit from a selective advantage in their interaction with the immune system, either during the course of an infection or in transmission to individuals with previous exposure to antigen. Analysis of amino acid usage at sites under positive selection indicates that this selective advantage can be conferred by amino acid substitutions that share physicochemically similar properties.

Spatio-temporal dynamics of the grey-sided vole in Hokkaido: identifying coupling using state-based Markov-chain modelling.

Explaining synchronization of cyclical or fluctuating populations over geographical regions presents ecologists with novel analytical challenges. We have developed a method to measure synchrony within spatial-temporal datasets of population densities applicable to both periodic and irregularly fluctuating populations. The dynamics of each constituent population is represented by a discrete Markov model. The state of a population trajectory at each time-point is classified as one of 'increase', 'decrease', 'peak' or 'trough'. The set of populations at any time-point is characterized by the frequency distribution of these different states, and the time-evolution of this frequency distribution used to test the hypothesis that the dynamics of each population proceeds independently of the others. The analysis identifies years in which population coupling results in synchronous states and onto which states the system converges, and identifies those years in which synchrony remains high but is accounted for by coupling observed in previous years. It also enables identification of which pairs of sites show the highest levels of coupling. Applying these methods to populations of the grey-sided vole on Hokkaido reveals them to be fluctuating in greater synchrony than would be expected from independent dynamics, and that this level of synchrony is maintained through intermittent coupling acting in ca. 1 year in four or five. High synchrony occurs between sites with similar vegetation and of similar altitude indicating that coupling may be mediated through shared environmental stimuli. When coupling is indicated, convergence is equally likely to occur on a peak state as a trough, indicating that synchronization may be brought about by the response of populations to a combination of different stimuli rather than by the action of any single process.

Habitat loss and raptor predation: disentangling long- and short-term causes of red grouse declines.

The number of red grouse (Lagopus lagopus scoticus) shot in the UK has declined by 50% during the 20th century This decline has coincided with reductions in the area of suitable habitat and recoveries in the populations of some avian predators. Here we use long-term records of shooting bags and a large-scale manipulation of raptor density to disentangle the effects of habitat loss and raptor predation on grouse populations. The numbers of grouse harvested on the Eskdale half of Langholm Moor in southern Scotland declined significantly during 1913-1990 and grouse bags from the whole moor from 1950 to 1990 exhibited an almost identical but non-significant trend. Hen harriers (Circus cyaneus) and peregrine falcons (Falco peregrinus) were absent or bred at low densities on this moor throughout this period but heather-dominant vegetation declined by 48% between 1948 and 1988. Harrier and peregrine breeding numbers on Langholm Moor increased to high levels following protection in 1990 whilst grouse density and grouse bags declined year after year until shooting was abandoned in 1998. The prediction of a peak in grouse bags on Langholm Moor in 1996 based on the patterns of bags during 1950-1990 was supported by the observed peaks in 1997 on two nearby moors with few raptors which formerly cycled in synchrony with Langholm Moor. This study demonstrates that, whilst long-term declines in grouse bags were most probably due to habitat loss, high levels of raptor predation subsequently limited the grouse population and suppressed a cycle. This study thus offers support to theoretical models which predict that generalist predators may suppress cycles in prey populations.

The construction and analysis of epidemic trees with reference to the 2001 UK foot-and-mouth outbreak.

The case-reproduction ratio for the spread of an infectious disease is a critically important concept for understanding dynamics of epidemics and for evaluating impact of control measures on spread of infection. Reliable estimation of this ratio is a problem central to epidemiology and is most often accomplished by fitting dynamic models to data and estimating combinations of parameters that equate to the case-reproduction ratio. Here, we develop a novel parameter-free method that permits direct estimation of the history of transmission events recoverable from detailed observation of a particular epidemic. From these reconstructed 'epidemic trees', case-reproduction ratios can be estimated directly. We develop a bootstrap algorithm that generates percentile intervals for these estimates that shows the procedure to be both precise and robust to possible uncertainties in the historical reconstruction. Identifying and 'pruning' branches from these trees whose occurrence might have been prevented by implementation of more stringent control measures permits estimation of the possible efficacy of these alternative measures. Examination of the cladistic structure of these trees as a function of the distance of each case from its infection source reveals useful insights about the relationship between long-distance transmission events and epidemic size. We demonstrate the utility of these methods by applying them to data from the 2001 foot-and-mouth disease outbreak in the UK.

Neighbourhood control policies and the spread of infectious diseases.

We present a model of a control programme for a disease outbreak in a population of livestock holdings. Control is achieved by culling infectious holdings when they are discovered and by the pre-emptive culling of livestock on holdings deemed to be at enhanced risk of infection. Because the pre-emptive control programme cannot directly identify exposed holdings, its implementation will result in the removal of both infected and uninfected holdings. This leads to a fundamental trade-off: increased levels of control produce a greater reduction in transmission by removing more exposed holdings, but increase the number of uninfected holdings culled. We derive an expression for the total number of holdings culled during the course of an outbreak and demonstrate that there is an optimal control policy, which minimizes this loss. Using a metapopulation model to incorporate local clustering of infection, we examine a neighbourhood control programme in a locally spreading outbreak. We find that there is an optimal level of control, which increases with increasing basic reproduction ratio, R(0); moreover, implementation of control may be optimal even when R(0) < 1. The total loss to the population is relatively insensitive to the level of control as it increases beyond the optimal level, suggesting that over-control is a safer policy than under-control.

The generation and persistence of genetic variation in foot-and-mouth disease virus.

Genetic variation in foot-and-mouth disease virus (FMDV) is of interest for at least two reasons. First, changes to the genes encoding capsid proteins results in antigenic variation, and affects vaccine efficiency and effectiveness of vaccination programs; second, genetic changes can lead to important insights into the transport of virus between countries, regions, herds, and even possibly individuals. Current estimates of RNA virus mutation rates suggest that an average of about one base mis-incorporation is likely to occur each time a single FMDV genome replicates. This should result in the introduction of every possible 1-step mutation from the progenitor genotype into the viraemia of a single infected animal many times a day. In the absence of purifying selection, a single infected animal should therefore generate a genetically very diverse population of virus.Viral-capsid sequences obtained from infected animals sampled over long-term FMDV epidemics suggest that these genetic changes accrue in a remarkably linear 'clock-like' fashion and at rates of around 1% change per year. While such a rate is generally regarded as quite high, it is actually somewhat lower than one might expect based on the rate at which viral diversity could be generated within a single animal. The difference might be explained in a variety of possible ways: (1) the mutation rate has been overestimated; (2) purifying selection is stronger than predicted; (3) only a restricted subset of excreted virus is actually infectious; (4) infected animals only excrete virus from a small partitioned subset of amplified virus, and that most of the generated viral diversity is unable to exit the animal; or (5) only a small fraction of all infected animals participate in the actual disease-transmission process.

The design of veterinary vaccination programmes.

The optimal design of a veterinary vaccination programme depends on both the characteristics of the vaccine and the epidemiology of the pathogen or parasite. Relevant vaccine characteristics are the proportion of those vaccinated that are initially protected, the duration of protection and the coverage achieved by the vaccination programme. The most important epidemiological parameter is the basic reproduction number, R0. Mathematical theory can integrate this information to address such questions as: whether it is possible to eliminate an infection; what proportion of hosts must be vaccinated to achieve this: what age should hosts first be vaccinated; and at what interval should hosts be revaccinated? Examples of rabies in foxes and foot-and-mouth disease in cattle suggest that theory can be used to guide the design of vaccination programmes.