Evolutionary Epidemiology of Drug-Resistance in Space

The spread of drug-resistant parasites erodes the efficacy of therapeutic treatments against many infectious diseases and is a major threat of the 21st century. The evolution of drug-resistance depends, among other things, on how the treatments are administered at the population level. “Resistance management” consists of finding optimal treatment strategies that both reduce the consequence of an infection at the individual host level, and limit the spread of drug-resistance in the pathogen population. Several studies have focused on the effect of mixing different treatments, or of alternating them in time. Here, we analyze another strategy, where the use of the drug varies spatially: there are places where no one receives any treatment. We find that such a spatial heterogeneity can totally prevent the rise of drug-resistance, provided that the size of treated patches is below a critical threshold. The range of parasite dispersal, the relative costs and benefits of being drug-resistant compared to being drug-sensitive, and the duration of an infection with drug-resistant parasites are the main factors determining the value of this threshold. Our analysis thus provides some general guidance regarding the optimal spatial use of drugs to prevent or limit the evolution of drug-resistance

Timing of Pathogen Adaptation to a Multicomponent Treatment

The sustainable use of multicomponent treatments such as combination therapies, combination vaccines/chemicals, and plants carrying multigenic resistance requires an understanding of how their population-wide deployment affects the speed of the pathogen adaptation. Here, we develop a stochastic model describing the emergence of a mutant pathogen and its dynamics in a heterogeneous host population split into various types by the management strategy. Based on a multi-type Markov birth and death process, the model can be used to provide a basic understanding of how the life-cycle parameters of the pathogen population, and the controllable parameters of a management strategy affect the speed at which a pathogen adapts to a multicomponent treatment. Our results reveal the importance of coupling stochastic mutation and migration processes, and illustrate how their stochasticity can alter our view of the principles of managing pathogen adaptive dynamics at the population level. In particular, we identify the growth and migration rates that allow pathogens to adapt to a multicomponent treatment even if it is deployed on only small proportions of the host. In contrast to the accepted view, our model suggests that treatment durability should not systematically be identified with mutation cost. We show also that associating a multicomponent treatment with defeated monocomponent treatments can be more durable than associating it with intermediate treatments including only some of the components. We conclude that the explicit modelling of stochastic processes underlying evolutionary dynamics could help to elucidate the principles of the sustainable use of multicomponent treatments in population-wide management strategies intended to impede the evolution of harmful populations.Comment: 3 figure

The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni

Natural selection acts on all organisms, including parasites, to maximize reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian state-space models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma mansoni may be limited by life-history costs not present in susceptible counterparts. S. mansoni parasites from a praziquantel-susceptible (S), a praziquantel-resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life-history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond

One Health – an Ecological and Evolutionary Framework for tackling Neglected Zoonotic Diseases

Understanding the complex population biology and transmission ecology of multihost parasites has been declared as one of the major challenges of biomedical sciences for the 21st century and the Neglected Zoonotic Diseases (NZDs) are perhaps the most neglected of all the Neglected Tropical Diseases (NTDs). Here we consider how multihost parasite transmission and evolutionary dynamics may affect the success of human and animal disease control programmes, particularly neglected diseases of the developing world. We review the different types of zoonotic interactions that occur, both ecological and evolutionary, their potential relevance for current human control activities, and make suggestions for the development of an empirical evidence base and theoretical framework to better understand and predict the outcome of such interactions. In particular, we consider whether preventive chemotherapy, the current mainstay of NTD control, can be successful without a One Health approach. Transmission within and between animal reservoirs and humans can have important ecological and evolutionary consequences, driving the evolution and establishment of drug resistance, as well as providing selective pressures for spill‐over, host switching, hybridizations and introgressions between animal and human parasites. Our aim here is to highlight the importance of both elucidating disease ecology, including identifying key hosts and tailoring control effort accordingly, and understanding parasite evolution, such as precisely how infectious agents may respond and adapt to anthropogenic change. Both elements are essential if we are to alleviate disease risks from NZDs in humans, domestic animals and wildlife

Phylogenetic surveillance of viral genetic diversity and the evolving molecular epidemiology of human immunodeficiency virus type 1

With ongoing generation of viral genetic diversity and increasing levels of migration, the global human immunodeficiency virus type 1 (HIV-1) epidemic is becoming increasingly heterogeneous. In this study, we investigate the epidemiological characteristics of 5,675 HIV-1 pol gene sequences sampled from distinct infections in the United Kingdom. These sequences were phylogenetically analyzed in conjunction with 976 complete-genome and 3,201 pol gene reference sequences sampled globally and representing the broad range of HIV-1 genetic diversity, allowing us to estimate the probable geographic origins of the various strains present in the United Kingdom. A statistical analysis of phylogenetic clustering in this data set identified several independent transmission chains within the United Kingdom involving recently introduced strains and indicated that strains more commonly associated with infections acquired heterosexually in East Africa are spreading among men who have sex with men. Coalescent approaches were also used and indicated that the transmission chains that we identify originated in the late 1980s to early 1990s. Similar changes in the epidemiological structuring of HIV epidemics are likely to be taking in place in other industrialized nations with large immigrant populations. The framework implemented here takes advantage of the vast amount of routinely generated HIV-1 sequence data and can provide epidemiological insights not readily obtainable through standard surveillance methods

The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni

Natural selection acts on all organisms, including parasites, to maximise reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian State-Space Models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma may be limited by life-history costs not present in susceptible counterparts. Schistosoma mansoni parasites from a praziquantel–susceptible (S), a praziquantel–resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond

PolyTB: a genomic variation map for Mycobacterium tuberculosis

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second major cause of death from an infectious disease worldwide. Recent advances in DNA sequencing are leading to the ability to generate whole genome information in clinical isolates of M. tuberculosis complex (MTBC). The identification of informative genetic variants such as phylogenetic markers and those associated with drug resistance or virulence will help barcode Mtb in the context of epidemiological, diagnostic and clinical studies. Mtb genomic datasets are increasingly available as raw sequences, which are potentially difficult and computer intensive to process, and compare across studies. Here we have processed the raw sequence data (>1500 isolates, eight studies) to compile a catalogue of SNPs (n = 74,039, 63% non-synonymous, 51.1% in more than one isolate, i.e. non-private), small indels (n = 4810) and larger structural variants (n = 800). We have developed the PolyTB web-based tool (http://pathogenseq.lshtm.ac.uk/polytb) to visualise the resulting variation and important meta-data (e.g. in silico inferred strain-types, location) within geographical map and phylogenetic views. This resource will allow researchers to identify polymorphisms within candidate genes of interest, as well as examine the genomic diversity and distribution of strains. PolyTB source code is freely available to researchers wishing to develop similar tools for their pathogen of interest

A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant staphylococcus aureus pandemic

The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens

Killing them softly:managing pathogen polymorphism and virulence in spatially variable environments

Understanding why pathogen populations are genetically variable is vital because genetic variation fuels evolution, which often hampers disease control efforts. Here I argue that classical models of evolution in spatially variable environments – specifically, models of hard and soft selection – provide a useful framework to understand the maintenance of pathogen polymorphism and the evolution of virulence. First, the similarities between models of hard and soft selection and pathogen life cycles are described, highlighting how the type and timing of pathogen control measures impose density regulation that may affect both the level of pathogen polymorphism and virulence. The article concludes with an outline of potential lines of future theoretical and experimental work

Evolution and Biogeography of Haemonchus contortus: Linking Faunal Dynamics in Space and Time

History is the foundation that informs about the nuances of faunal assembly that are essential in understanding the dynamic nature of the host-parasite interface. All of our knowledge begins and ends with evolution, ecology and biogeography, as these interacting facets determine the history of biodiverse systems. These components, relating to Haemonchus, can inform about the complex history of geographical distribution, host association and the intricacies of host-parasite associations that are played out in physiological and behavioural processes that influence the potential for disease and our capacity for effective control in a rapidly changing world. Origins and evolutionary diversification among species of the genus Haemonchus and Hae- monchus contortus occurred in a complex crucible defined by shifts in environmental structure emerging from cycles of climate change and ecological perturbation during the late Tertiary and through the Quaternary. A history of sequential host colonization associated with waves of dispersal bringing assemblages of ungulates from Eurasia into Africa and processes emerging from ecosystems in collision and faunal turnover defined the arena for radiation among 12 recognized species of Haemonchus. Among congeners, the host range for H. contortus is exceptionally broad, including species among artiodactyls of 40 genera representing 5 families (and within 12 tribes of Bovi- dae). Broad host range is dramatically reflected in the degree to which translocation, introduction and invasion with host switching, has characterized an expanding distribution over time in North America, South America, southern Eurasia, Australia and New Zealand, coincidental with agriculture, husbandry and global colonization by human populations driven particularly by European exploration after the 1500s. African origins in xeric to mesic habitats of the African savannah suggest that historical constraints linked to ecological adaptations (tolerances and developmental thresholds defined by temperature and humidity for larval stages) will be substantial determinants in the potential outcomes for widespread geographical and host colonization which are predicted to unfold over the coming century. Insights about deeper evolutionary events, ecology and biogeography are critical as understanding history informs us about the possible range of responses in complex systems under new regimes of environmental forcing, especially, in this case, ecological perturbation linked to climate change. A deeper history of perturbation is relevant in understanding contemporary systems that are now strongly structured by events of invasion and colonization. The relaxation of abiotic and biotic controls on the occurrence of H. contortus, coincidental with inception and dissemination of anthelmintic resistance may be synergistic, serving to exacerbate challenges to control parasites or to limit the socioeconomic impacts of infection that can influence food security and availability. Studies of haemonchine nematodes contribute directly to an expanding model about the nature of diversity and the evolutionary trajectories for faunal assembly among complex hosteparasite systems across considerable spatial and temporal scales