The 2012 Madeira dengue outbreak: epidemiological determinants and future epidemic potential

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tDengue, a vector-borne viral disease of increasing global importance, is classically associated with tropical and sub-tropical regions around the world. Urbanisation, globalisation and climate trends, however, are facilitating the geographic spread of its mosquito vectors, thereby increasing the risk of the virus establishing itself in previously unaffected areas and causing large-scale epidemics. On 3 October 2012, two autochthonous dengue infections were reported within the Autonomous Region of Madeira, Portugal. During the following seven months, this first 'European' dengue outbreak caused more than 2000 local cases and 81 exported cases to mainland Europe. Here, using an ento-epidemiological mathematical framework, we estimate that the introduction of dengue to Madeira occurred around a month before the first official cases, during the period of maximum influx of airline travel, and that the naturally declining temperatures of autumn were the determining factor for the outbreak's demise in early December 2012. Using key estimates, together with local climate data, we further propose that there is little support for dengue endemicity on this island, but a high potential for future epidemic outbreaks when seeded between May and August-a period when detection of imported cases is crucial for Madeira's public health planning.The work was funded by the Royal Society (URF to MR)

Maintenance of phenotypic diversity within a set of virulence encoding genes of the malaria parasite Plasmodium falciparum

Open access article This is the final version of the article. Available from the publisher via the DOI in this record.Infection by the human malaria parasite Plasmodium falciparum results in a broad spectrum of clinical outcomes, ranging from severe and potentially life-threatening malaria to asymptomatic carriage. In a process of naturally acquired immunity, individuals living in malaria-endemic regions build up a level of clinical protection, which attenuates infection severity in an exposure-dependent manner. Underlying this shift in the immunoepidemiology as well as the observed range in malaria pathogenesis is the var multigene family and the phenotypic diversity embedded within. The var gene-encoded surface proteins Plasmodium falciparum erythrocyte membrane protein 1 mediate variant-specific binding of infected red blood cells to a diverse set of host receptors that has been linked to specific disease manifestations, including cerebral and pregnancy-associated malaria. Here, we show that cross-reactive immune responses, which minimize the within-host benefit of each additionally expressed gene during infection, can cause selection for maximum phenotypic diversity at the genome level. We further show that differential functional constraints on protein diversification stably maintain uneven ratios between phenotypic groups, in line with empirical observation. Our results thus suggest that the maintenance of phenotypic diversity within P. falciparum is driven by an evolutionary trade-off that optimizes between within-host parasite fitness and between-host selection pressure.Royal Society - University Research Fellowshi

Natural, persistent oscillations in a spatial multi-strain disease system with application to dengue.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Many infectious diseases are not maintained in a state of equilibrium but exhibit significant fluctuations in prevalence over time. For pathogens that consist of multiple antigenic types or strains, such as influenza, malaria or dengue, these fluctuations often take on the form of regular or irregular epidemic outbreaks in addition to oscillatory prevalence levels of the constituent strains. To explain the observed temporal dynamics and structuring in pathogen populations, epidemiological multi-strain models have commonly evoked strong immune interactions between strains as the predominant driver. Here, with specific reference to dengue, we show how spatially explicit, multi-strain systems can exhibit all of the described epidemiological dynamics even in the absence of immune competition. Instead, amplification of natural stochastic differences in disease transmission, can give rise to persistent oscillations comprising semi-regular epidemic outbreaks and sequential dominance of dengue's four serotypes. Not only can this mechanism explain observed differences in serotype and disease distributions between neighbouring geographical areas, it also has important implications for inferring the nature and epidemiological consequences of immune mediated competition in multi-strain pathogen systems.Fundacao para a Ciencia e TecnologiaSiemens PortugalRoyal Societ

Erasing the Epigenetic Memory and Beginning to Switch—The Onset of Antigenic Switching of var Genes in Plasmodium falciparum

Antigenic variation in Plasmodium falciparum is regulated by transcriptional switches among members of the var gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no var background, similar to merozoites that egress from the liver where no var gene is expressed. Creating a null-var background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, var transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA vars, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent in vitro switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type per se but on intrinsic properties of each gene. We concluded that var switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in var transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching

Quantitative host resistance drives the evolution of increased virulence in an emerging pathogen

Emergent infectious diseases can have a devastating impact on host populations. The high selective pressures on both the hosts and the pathogens frequently lead to rapid adaptations not only in pathogen virulence but also host resistance following an initial outbreak. However, it is often unclear whether hosts will evolve to avoid infection‐associated fitness costs by preventing the establishment of infection (here referred to as qualitative resistance ) or by limiting its deleterious effects through immune functioning (here referred to as quantitative resistance ). Equally, the evolutionary repercussions these different resistance mechanisms have for the pathogen are often unknown. Here, we investigate the co‐evolutionary dynamics of pathogen virulence and host resistance following the epizootic outbreak of the highly pathogenic bacterium Mycoplasma gallisepticum in North American house finches (Haemorhous mexicanus ). Using an evolutionary modelling approach and with a specific emphasis on the evolved resistance trait, we demonstrate that the rapid increase in the frequency of resistant birds following the outbreak is indicative of strong selection pressure to reduce infection‐associated mortality. This, in turn, created the ecological conditions that selected for increased bacterial virulence. Our results thus suggest that quantitative host resistance was the key factor underlying the evolutionary interactions in this natural host–pathogen system.Publisher PDFPeer reviewe

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

Assessing the burden of pregnancy-associated malaria under changing transmission settings

BACKGROUND: The clinical presentation of pregnancy-associated malaria, or PAM, depends crucially on the particular epidemiological settings. This can potentially lead to an underestimation of its overall burden on the female population, especially in regions prone to epidemic outbreaks and where malaria transmission is generally low. METHODS: Here, by re-examining historical data, it is demonstrated how excess female mortality can be used to evaluate the burden of PAM. A simple mathematical model is then developed to highlight the contrasting signatures of PAM within the endemicity spectrum and to show how PAM is influenced by the intensity and stability of transmission. RESULTS: Both the data and the model show that maternal malaria has a huge impact on the female population. This is particularly pronounced in low-transmission settings during epidemic outbreaks where excess female mortality/morbidity can by far exceed that of a similar endemic setting. CONCLUSION: The results presented here call for active intervention measures not only in highly endemic regions but also, or in particular, in areas where malaria transmission is low and seasonal

The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tAntigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum, we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene's activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria. DOI:http://dx.doi.org/10.7554/eLife.01074.001.The work was funded by the Wellcome Trust (Grant No. 082130/Z/07/Z to CN), the Biotechnology and Biological Sciences Research Council (studentship to RN) and the Royal Society (University Research Fellowship to MR)

Individual bacteria in structured environments rely on phenotypic resistance to phage

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: All relevant data are within the paper and its Supporting Information files.Bacteriophages represent an avenue to overcome the current antibiotic resistance crisis, but evolution of genetic resistance to phages remains a concern. In vitro, bacteria evolve genetic resistance, preventing phage adsorption or degrading phage DNA. In natural environments, evolved resistance is lower possibly because the spatial heterogeneity within biofilms, microcolonies, or wall populations favours phenotypic survival to lytic phages. However, it is also possible that the persistence of genetically sensitive bacteria is due to less efficient phage amplification in natural environments, the existence of refuges where bacteria can hide, and a reduced spread of resistant genotypes. Here, we monitor the interactions between individual planktonic bacteria in isolation in ephemeral refuges and bacteriophage by tracking the survival of individual cells. We find that in these transient spatial refuges, phenotypic resistance due to reduced expression of the phage receptor is a key determinant of bacterial survival. This survival strategy is in contrast with the emergence of genetic resistance in the absence of ephemeral refuges in well-mixed environments. Predictions generated via a mathematical modelling framework to track bacterial response to phages reveal that the presence of spatial refuges leads to fundamentally different population dynamics that should be considered in order to predict and manipulate the evolutionary and ecological dynamics of bacteria-phage interactions in naturally structured environments.Medical Research Council (MRC)Engineering and Physical Sciences Research Council (EPSRC)Gordon and Betty and Gordon Moore FoundationEuropean Research Council (ERC)Biotechnology and Biological Sciences Research Council (BBSRC)Natural Environment Research Council (NERC)Marie Skłodowska-Curie ActionsDefence Science and Technology Laboratory (Dstl)Royal Societ

A Statistically Rigorous Method for Determining Antigenic Switching Networks

Many vector-borne pathogens rely on antigenic variation to prolong infections and increase their likelihood of onward transmission. This immune evasion strategy often involves mutually exclusive switching between members of gene families that encode functionally similar but antigenically different variants during the course of a single infection. Studies of different pathogens have suggested that switching between variant genes is non-random and that genes have intrinsic probabilities of being activated or silenced. These factors could create a hierarchy of gene expression with important implications for both infection dynamics and the acquisition of protective immunity. Inferring complete switching networks from gene transcription data is problematic, however, because of the high dimensionality of the system and uncertainty in the data. Here we present a statistically rigorous method for analysing temporal gene transcription data to reconstruct an underlying switching network. Using artificially generated transcription profiles together with in vitro var gene transcript data from two Plasmodium falciparum laboratory strains, we show that instead of relying on data from long-term parasite cultures, accuracy can be greatly improved by using transcription time courses of several parasite populations from the same isolate, each starting with different variant distributions. The method further provides explicit indications about the reliability of the resulting networks and can thus be used to test competing hypotheses with regards to the underlying switching pathways. Our results demonstrate that antigenic switch pathways can be determined reliably from short gene transcription profiles assessing multiple time points, even when subject to moderate levels of experimental error. This should yield important new information about switching patterns in antigenically variable organisms and might help to shed light on the molecular basis of antigenic variation