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56 results for “within-host”
Evaluating the contributions of purifying selection and progeny-skew in dictating within-host Mycobacterium tuberculosis evolution
<p class="BodyA"><span><span><span><span><span><span><span><span><span><span>The within-host evolutionary dynamics of TB remain unclear, and underlying biological characteristics render standard population genetic approaches based upon the Wright-Fisher model largely inappropriate. In addition, the compact genome combined with an absence of recombination is expected to result in strong purifying selection effects. Thus, it is imperative to establish a biologically-relevant evolutionary framework incorporating these factors in order to enable an accurate study of this important human pathogen. Further, such a model is critical for inferring fundamental evolutionary parameters related to patient treatment, including mutation rates and the severity of infection bottlenecks. We here implement such a model and infer the underlying evolutionary parameters governing within-patient evolutionary dynamics. Results demonstrate that the progeny skew associated with the clonal nature of TB severely reduces genetic diversity and that the neglect of this parameter in previous studies has led to significant mis-inference of mutation rates. As such, our results suggest an underlying <i>de novo</i> mutation rate that is considerably faster than previously inferred, and a progeny distribution differing significantly from Wright-Fisher assumptions. This inference represents a more appropriate evolutionary null model, against which the periodic effects of positive selection, associated with drug-resistance for example, may be better assessed.</span></span></span></span></span></span></span></span></span></span></p>
Data from: Predators and patterns of within-host growth can mediate both among-host competition and the evolution of transmission potential of parasites
Parasite prevalence shows tremendous spatiotemporal variation. Theory indicates this variation might stem from life history characteristics of parasites and key ecological factors. Here, we illustrate how the interaction of an important predator and the schedule of 'transmission potential' of two parasites can explain parasite abundance. A field survey showed that a non-castrating fungus (Metschnikowia bicuspidata) commonly infected a dominant zooplankton host (Daphnia dentifera), while a castrating bacterial parasite (Pasteuria ramosa) was rare. This result seemed surprising given that the bacterium produces many more infectious propagules (spores) than the fungus upon host death. The fungus's dominance can be explained by the schedule of within host growth of parasites (i.e., how transmission potential changes over the course of infection) and spore release from 'sloppy predators' (Chaoborus spp., who consume Daphnia prey whole, then later regurgitate the carapace and parasite spores). In essence, sloppy predators create a niche that the faster-schedule fungus currently occupies. However, a selection experiment showed the slower-schedule bacterium can evolve into this faster-schedule, predator-mediated niche (but pays a cost in maximal spore yield to do so). Hence, our study shows how parasite life history can interact with predation to strongly influence the ecology, epidemiology, and evolution of infectious disease. 18 pages, 1 table, 5 figures; Appendix
Data from: A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity
Phylogenetics is a powerful tool for understanding the diversification dynamics of viral pathogens. Here we present an extension of the spectral density profile of the modified graph Laplacian, which facilitates the characterization of within-host molecular evolution of viruses and the direct comparison of diversification dynamics between hosts. This approach is non-parametric and therefore fast and model-free. We used simulations of within-host evolutionary scenarios to evaluate the efficiency of our approach and to demonstrate the significance of interpreting a viral phylogeny by its spectral density profile in terms of diversification dynamics. The key features that are captured by the profile are positive selection on the viral gene (or genome), temporal changes in substitution rates, mutational fitness, and time between sampling. Using sequences from individuals infected with HIV-1, we showed the utility of this approach for characterizing within-host diversification dynamics, for comparing dynamics between hosts, and for charting disease progression in infected individuals sampled over multiple years. We furthermore propose a heuristic test for assessing founder heterogeneity, which allows us to classify infections with single and multiple HIV-1 founder viruses. This non-parametric approach can be a valuable complement to existing parametric approaches.
Within-host priority effects and epidemic timing determine outbreak severity in coinfected populations
Coinfections of hosts by multiple pathogen species are ubiquitous, but predicting their impact on disease remains challenging. Interactions between coinfecting pathogens within hosts can alter pathogen transmission, with the impact on transmission typically dependent on the relative arrival order of pathogens within hosts (within-host priority effects). However, it is unclear how these within-host priority effects influence multi-pathogen epidemics, particularly when the arrival order of pathogens at the host population scale varies. Here we combined models and experiments with zooplankton and their naturally co-occurring fungal and bacterial pathogens to examine how within-host priority effects influence multi-pathogen epidemics. Epidemiological models parameterized with within-host priority effects measured at the single host scale predicted that advancing the start date of bacterial epidemics relative to fungal epidemics would decrease mean bacterial prevalence in a multi-pathogen setting, while models without within-host priority effects predicted the opposite effect. We tested these predictions with experimental multi-pathogen epidemics. Empirical dynamics matched predictions from the model including within-host priority effects, providing evidence that within-host priority effects influenced epidemic dynamics. Overall, within-host priority effects may be a key element of predicting multi-pathogen epidemic dynamics in the future, particularly as shifting disease phenology alters the order of infection within hosts.
Data Source file for manuscript: Within-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients
<p>ABSTRACT</p><p>Infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-PE) are associated with excess morbidity and mortality. Despite recognition of this immediate impact on human health, essential aspects of their molecular epidemiology remain under-investigated. This includes knowledge on the potential of a particular strain to persist in a host, mutational events during colonization, and the genetic diversity in individual patients over time. To investigate long-term genetic diversity of colonizing and infecting ESBL-producing <i>Klebsiella pneumoniae </i>species complex and ESBL-<i>Escherichia coli</i> in individual patients over time, we conducted performed a ten-year longitudinal retrospective study and extracted clinical and microbiological data from electronic health records. In this investigation, 76 ESBL-<i>K. pneumoniae</i> species complex and 284 ESBL-<i>E. coli</i> isolates were recovered from 19 and 61 patients. Strain persistence was detected in all patients colonized with ESBL-<i>K. pneumoniae </i>species complex, and 83.6% of patients colonized with ES BL-<i>E. coli</i>. Antimicrobial resistance genes, plasmid replicons, and whole ESBL-plasmids were shared between isolates regardless of chromosomal relatedness. Our study suggests that patients colonized with ESBL-producers may act as durable reservoirs for ongoing transmission of ESBLs, and that they are at a prolonged risk of recurrent infection with colonizing strains.</p><p>DATA SOURCE FILE</p><p>In this Data Source file, you will find access to the raw data, metadata and results obtained during the study: "Within-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients". Data is organized following the structure of Figures/Tables of the manuscript and Supplementary Material. Additional figures not included in the main manuscript nor in the Supplementary Material are also available.</p><p>All sequencing and sample data from this study can be accessed at the NCBI database under the BioProject number PRJNA910977: <a href="http://dataview.ncbi.nlm.nih.gov/object/PRJNA910977">http://dataview.ncbi.nlm.nih.gov/object/PRJNA910977. </a>No new software was developed during this study. Standard bioinformatics software was used and the commands used can be accessed at the Supplementary Information file.</p>
Evaluating the contributions of purifying selection and progeny-skew in dictating within-host Mycobacterium tuberculosis evolution
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Data from: A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity
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Data from: Predators and patterns of within-host growth can mediate both among-host competition and the evolution of transmission potential of parasites
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Data from: Alternative paths to success in a parasite community: within-host competition can favor higher virulence or direct interference
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Within-host priority effects and epidemic timing determine outbreak severity in coinfected populations
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Data from: Within-host priority effects systematically alter pathogen coexistence
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Data from: Within-host competition between Borrelia afzelii ospC strains in wild hosts as revealed by massively parallel amplicon sequencing
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Data from: Within-host stochastic emergence dynamics of immune-escape mutants
Predicting the emergence of new pathogenic strains is a key goal of evolutionary epidemiology. However, the majority of existing studies have focussed on emergence at the population level, and not within a host. In particular, the coexistence of pre-existing and mutated strains triggers a heightened immune response due to the larger total pathogen population; this feedback can smother mutated strains before they reach an ample size and establish. Here, we extend previous work for measuring emergence probabilities in non-equilibrium populations, to within-host models of acute infections. We create a mathematical model to investigate the emergence probability of a fitter strain if it mutates from a self-limiting strain that is guaranteed to go extinct in the long-term. We show that ongoing immune cell proliferation during the initial stages of infection causes a drastic reduction in the probability of emergence of mutated strains; we further outline how this effect can be accurately measured. Further analysis of the model shows that, in the short-term, mutant strains that enlarge their replication rate due to evolving an increased growth rate are more favoured than strains that suffer a lower immune-mediated death rate ('immune tolerance'), as the latter does not completely evade ongoing immune proliferation due to inter-parasitic competition. We end by discussing the model in relation to within-host evolution of human pathogens (including HIV, hepatitis C virus, and cancer), and how ongoing immune growth can affect their evolutionary dynamics.
Data from: Multiple-strain infections of borrelia afzelii: a role for within-host interactions in the maintenance of antigenic diversity?
Genetically diverse infections are common but little is known about what effects coinfecting strains have on each other in natural host-parasite systems. To explore the nature and consequences of interactions in the wild, we studied the tick-transmitted bacterium Borrelia afzelii in one of its main reservoir hosts, the bank vole Myodes glareolus. We measured overall infection intensity with quantitative polymerase chain reaction (PCR) and resolved the composition of multiple infections using strain-specific PCR assays targeting the ospC gene (which encodes an immunodominant surface protein). We found seven different strains, as defined by ospC genotype. There was little evidence for interactions affecting infection intensities, but strains were highly aggregated (i.e., there were more multiple infections than expected from random co-occurrence). Moreover, there was a positive correlation between the difference at the amino acid level between two OspC types and their degree of association. Overall, the observed patterns suggest that facilitation is more important than competition in this system and that more diverse infections have an advantage in establishing and/or maintaining infection. We propose that this advantage is one of the factors that favors antigenic diversity.
Data from: The impact of within-host ecology on the fitness of a drug-resistant parasite
Background and objectives: The rate of evolution of drug resistance depends on the fitness of resistant pathogens. The fitness of resistant pathogens is reduced by competition with sensitive pathogens in untreated hosts and so enhanced by competitive release in drug-treated hosts. We set out to estimate the magnitude of those effects on a variety of fitness measures, hypothesizing that competitive suppression and competitive release would have larger impacts when resistance was rarer to begin with. Methodology: We infected mice with varying densities of drug-resistant Plasmodium chabaudi malaria parasites in a fixed density of drug-sensitive parasites and followed infection dynamics using strain-specific quantitative PCR. Results: Competition with susceptible parasites reduced the absolute fitness of resistant parasites by 50-100%. Drug treatment increased the absolute fitness from 2- to >10 000-fold. The ecological context and choice of fitness measure was responsible for the wide variation in those estimates. Initial population growth rates poorly predicted parasite abundance and transmission probabilities. Conclusions and implications: (i) The sensitivity of estimates of pathogen fitness to ecological context and choice of fitness measure make it difficult to derive field-relevant estimates of the fitness costs and benefits of resistance from experimental settings. (ii) Competitive suppression can be a key force preventing resistance from emerging when it is rare, as it is when it first arises. (iii) Drug treatment profoundly affects the fitness of resistance. Resistance evolution could be slowed by developing drug use policies that consider in-host competition.
Data from: Within-host competition in genetically diverse malaria infections: parasite virulence and competitive success.
Humans and animals often become coinfected with pathogen strains that differ in virulence. The ensuing interaction between these strains can, in theory, be a major determinant of the direction of selection on virulence genes in pathogen populations. Many mathematical analyses of this assume that virulent pathogen lineages have a competitive advantage within coinfected hosts and thus predict that pathogens will evolve to become more virulent where genetically diverse infections are common. Although the implications of these studies are relevant to both fundamental biology and medical science, direct empirical tests for relationships between virulence and competitive ability are lacking. Here we use newly developed strain-specific real-time quantitative polymerase chain reaction protocols to determine the pairwise competitiveness of genetically divergent Plasmodium chabaudi clones that represent a wide range of innate virulences in their rodent host. We found that even against their background of widely varying genotypic and antigenic properties, virulent clones had a competitive advantage in the acute phase of mixed infections. The more virulent a clone was relative to its competitor, the less it suffered from competition. This result confirms our earlier work with parasite lines derived from a single clonal lineage by serial passage and supports the virulence-competitive ability assumption of many theoretical models. To the extent that our rodent model captures the essence of the natural history of malaria parasites, public health interventions which reduce the incidence of mixed malaria infections should have beneficial consequences by reducing the selection for high virulence.
Data from: The within-host dynamics of infection in trans-generationally primed flour beetles
Many taxa exhibit plastic immune responses initiated after primary microbial exposure that provide increased protection against disease-induced mortality and the fitness costs of infection. In several arthropod species, this protection can even be passed from parents to offspring through a phenomenon called trans-generational immune priming. Here, we first demonstrate that trans-generational priming is a repeatable phenomenon in flour beetles (Tribolium castaneum) primed and infected with Bacillus thuringiensis (Bt). We then quantify the within-host dynamics of microbes and host physiological responses in infected offspring from primed and unprimed mothers by monitoring bacterial density and using mRNA-seq to profile host gene expression, respectively, over the acute infection period. We find that priming increases inducible resistance against Bt around a critical temporal juncture where host septicaemic trajectories, and consequently survival, may be determined in unprimed individuals. Our results identify a highly differentially expressed biomarker of priming, containing an EIF4-e domain, in uninfected individuals, as well as several other candidate genes. Moreover, the induction and decay dynamics of gene expression over time suggest a metabolic shift in primed individuals. The identified bacterial and gene expression dynamics are likely to influence patterns of bacterial fitness and disease transmission in natural populations.
Data from: Resource limitation prevents the emergence of drug resistance by intensifying within-host competition
Slowing the evolution of antimicrobial resistance is essential if we are to continue to successfully treat infectious diseases. Whether a drug-resistant mutant grows to high densities, and so sickens the patient and spreads to new hosts, is determined by the competitive interactions it has with drug-susceptible pathogens within the host. Competitive interactions thus represent a good target for resistance management strategies. Using an in vivo model of malaria infection, we show that limiting a resource that is disproportionately required by resistant parasites retards the evolution of drug resistance by intensifying competitive interactions between susceptible and resistant parasites. Resource limitation prevented resistance emergence regardless of whether resistant mutants arose de novo or were experimentally added before drug treatment. Our work provides proof of principle that chemotherapy paired with an "ecological" intervention can slow the evolution of resistance to antimicrobial drugs, even when resistant pathogens are present at high frequencies. It also suggests that a broad range of previously untapped compounds could be used for treating infectious diseases.
Fits and plot data for the paper: "Combined analyses of within-host SARS-CoV-2 viral kinetics and information on past exposures to the virus in a human cohort identifies intrinsic differences of Omicron and Delta variants"
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Fig. 6 in Outcome of within-host competition demonstrates that parasite virulence doesn't equal success in a myxozoan model system
Fig. 6. Log fold change in immunogloblulin expression relative to controls on day 14 in intestine samples. Parasite copy numbers measured in intestine samples are overlaid on IgM intestine plot (parasite copy number data are the same for the IgT plot). Letters denote treatments that differed (Tukey's HSD tests, α = 0.05).
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Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
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DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.