Biology subjects

Lloyd, A.

Publications and source records attributed to Lloyd, A..

11 recordsLinked to original sources

bioRxiv2024

SUPPRESSION OF AEDES AEGYPTI BY STERILE INSECT TECHNIQUE (SIT) ON CAPTIVA ISLAND, FLORIDA, USA FROM 2020 TO 2022

Aedes aegypti, an aggressive nuisance biter and the primary vector for numerous arboviruses, such as chikungunya, dengue, and Zika, presents significant control challenges due to its ability to thrive in urban environments, escapes insecticide treatment by using cryptic resting and oviposition sites, and development of resistance to chemical mosquito control products being used routinely. To test a new approach in their integrative mosquito management toolbox. From 2020 to 2022, the Lee County Mosquito Control District (LCMCD) employed the Sterile Insect Technique (SIT) to test a new approach in its integrated mosquito management toolbox, targeting the population suppression of Ae. aegypti on Captiva Island, Florida. Over 24.1 million sterile males were released across three phases, covering up to 142 hectares. The study demonstrated a population reduction of up to 79% in wild adults and a 59% decline in egg densities in the primary intervention area. While population control was successful, an influx of wild females from untreated zones posed ongoing challenges to complete suppression in areas close to non-intervention areas. This supported a need for an area-wide integrated pest management (AW-IPM) approach. These results underscore SITs potential as a critical tool in integrated mosquito management strategies and emphasize practical application.

ecology↗

bioRxiv2024

Temporal dynamics of viral fitness and the adaptive immune response in HCV infection

Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. However, this generic definition can be further divided into two categories where intrinsic fitness describes the viral fitness without the influence of any immune pressure and effective fitness considers both intrinsic fitness with the influence of host immune pressure. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.

immunology↗

bioRxiv2023

Conserved allomorphs of MR1 drive specificity of MR1-restricted TCRs

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, has until recently been reported to be monomorphic. Tumor cell-specific MR1 restricted T cell receptors (TCRs) have been described, offering potential therapeutic application for cancer treatment. We show that human T cells expressing a TCR derived from an MR1-restricted T cell clone, termed MC.7.G5 (7G5.TCRT), retain MR1-directed cytotoxicity. However, activity is not pan-cancer, as initially reported with the clone MC.7.G5. Recognition is restricted by an allelic variant of MR1 (MR1*04) which is present at approximately 1% of the population at the heterozygote level. The 7G5 TCR is not cancer specific, as 7G5.TCRT and 7G5.TCRT-like TCRs react to both cancer and healthy cells expressing MR1*04 alleles. These data demonstrate that healthy individuals can harbor T cells reactive to an MR1 variant displaying self-ligands expressed in cancer and benign tissues. Targeting MR1 in cancer will require identification of cancer-specific presented ligands, and careful confirmation of cancer specificity of TCRs. MR1*04 may behave as an alloantigen warranting further study.

cancer biology↗

bioRxiv2021

Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells

T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-{gamma} response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections. One sentence summaryProgenitors of T-cell exhaustion in acute HCV infection

immunology↗

bioRxiv2019

After the Honeymoon, the Divorce: Unexpected Outcomes of Disease Control Measures Against Endemic Infections

The lack of effective vaccines for many endemic diseases often forces policymakers to enact control programs that rely on non-immunizing controls, such as vector control, in order to reduce the massive burden of these diseases. It is well known that controls can have counterintuitive effects, such as the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected for an infection near its endemic equilibrium, but also large outbreaks during control as a result of accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are not well understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without the control measures, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control - the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in model results from a number of settings when non-immunizing controls are used against an infection that confers immunity. Finally, we also examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches. Author SummaryMany common endemic infections lack effective, inexpensive vaccinations, and control relies instead on transmission reduction, e.g. mosquito population reduction for dengue. Often, these controls are used with the immediate goal of decreasing the current incidence with little importance placed on what will happen at later points in time, and much less what will happen once the control is stopped. Here, by looking at the cumulative incidence since the beginning of the control period, instead of the instantaneous incidence, we show that when controls are stopped, or fail, the resulting outbreaks can be large enough to completely eliminate any benefit of the control. We call this result the divorce effect. Further, we show that this result is not limited to specific transmission pathways or epidemiological parameters, but is instead tied directly to the reduction of herd immunity inherent in non-immunizing controls. Lastly, by evaluating programs to minimize the magnitude of the divorce effect, we show that without maintaining herd immunity, or successfully continuing control for decades, it is impossible to keep the costs of post-control outbreaks from outweighing the benefits of the control program.

epidemiology↗

bioRxiv2019

Locally Fixed Alleles: A method to localize gene drive to island populations

Invasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the \"Locally Fixed Alleles\" approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to multiple genomic alleles becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.

evolutionary biology↗

bioRxiv2018

Assessing the response of small RNA populations to allopolyploidy using resynthesized Brassica napus allotetraploids

Allopolyploidy, combining interspecific hybridization with whole genome duplication, has had significant impact on plant evolution. Its evolutionary success is related to the rapid and profound genome reorganizations that allow neo-allopolyploids to form and adapt. Nevertheless, how neo-allopolyploid genomes adapt to regulate their expression remains poorly understood. The hypothesis of a major role for small non-coding RNAs (sRNAs) in mediating the transcriptional response of neo-allopolyploid genomes has progressively emerged. Generally, 21-nt sRNAs mediate post-transcriptional gene silencing (PTGS) by mRNA cleavage whereas 24-nt sRNAs repress transcription (transcriptional gene silencing, TGS) through epigenetic modifications. Here, we characterize the global response of sRNAs to allopolyploidy in Brassica, using three independently resynthesized B. napus allotetraploids surveyed at two different generations in comparison with their diploid progenitors. Our results suggest an immediate but transient response of specific sRNA populations to allopolyploidy. These sRNA populations mainly target non-coding components of the genome but also target the transcriptional regulation of genes involved in response to stresses and in metabolism; this suggests a broad role in adapting to allopolyploidy. We finally identify the early accumulation of both 21- and 24-nt sRNAs involved in regulating the same targets, supporting a PTGS-to-TGS shift at the first stages of the neo-allopolyploid formation. We propose that reorganization of sRNA production is an early response to allopolyploidy in order to control the transcriptional reactivation of various non-coding elements and stress-related genes, thus ensuring genome stability during the first steps of neo-allopolyploid formation.

evolutionary biology↗

bioRxiv2018

Modelling sex-specific crossover patterning in Arabidopsis

Interference is a major force governing the patterning of meiotic crossovers. A leading model describing how interference influences crossover-patterning is the beam film model, a mechanical model based on the accumulation and redistribution of crossover-promoting stress along the chromosome axis. We use the beam-film model in conjunction with a large Arabidopsis reciprocal back-cross data set to gain mechanistic insights into the differences between male and female meiosis and crossover patterning. Beam-film modelling suggests that the underlying mechanics of crossover patterning and interference are identical in the two sexes, with the large difference in recombination rates and distributions able to be entirely explained by the shorter chromosome axes in females. The modelling supports previous indications that fewer crossovers occur via the class II pathway in female meiosis and that this could be explained by reduced DNA double strand breaks in female meiosis, paralleling the observed reduction in synaptonemal complex length between the two sexes. We also demonstrate that changes in the strength of suppression of neighboring class I crossovers can have opposite effects on effective interference depending on the distance between two genetic intervals.

genetics↗

bioRxiv2017

The Basic Reproductive Number for Disease Systems with Multiple Coupled Heterogeneities

In mathematical epidemiology, a well-known formula describes the impact of heterogeneity on the basic reproductive number, R0, for situations in which transmission is separable and for which there is one source of variation in susceptibility and one source of variation in infectiousness. This formula is written in terms of the magnitudes of the heterogeneities, as quantified by their coefficients of variation, and the correlation between them. A natural question to ask is whether analogous results apply when there are multiple sources of variation in susceptibility and/or infectiousness. In this paper we demonstrate that with three or more coupled heterogeneities, R0 under separable transmission depends on details of the distribution of the heterogeneities in a way that is not seen in the well-known simpler situation. We provide explicit formulae for the cases of multivariate normal and multivariate log-normal distributions, showing that R0 can again be expressed in terms of the magnitudes of the heterogeneities and the pairwise correlations between them. The formulae, however, differ between the two multivariate distributions, demonstrating that no formula of this type applies generally when there are three or more coupled heterogeneities. We see that the results of the formulae are approximately equal when heterogeneities are relatively small and show that an earlier result in the literature (Koella, 1991) should be viewed in this light. We provide numerical illustrations of our results and discuss a setting in which coupled heterogeneities are likely to have a major impact on the value of R0. We also describe a rather surprising result: in a system with three heterogeneities, R0 can exhibit non-monotonic behavior with increasing levels of heterogeneity, in marked contrast to the familiar two heterogeneity setting in which R0 either increases or decreases with increasing heterogeneity.

epidemiology↗

bioRxiv2017

Evaluating Strategies For Reversing CRISPR-Cas9 Gene Drives

A gene drive biases inheritance of a gene so that it increases in frequency within a population even when the gene confers no fitness benefit. There has been renewed interest in environmental releases of engineered gene drives due to recent proof of principle experiments with the CRISPR-Cas9 system as a drive mechanism. Release of modified organisms, however, is controversial, especially when the drive mechanism could theoretically alter all individuals of a species. Thus, it is desirable to have countermeasures to reverse a drive if a problem arises. Several genetic mechanisms for limiting or eliminating gene drives have been proposed and/or developed, including synthetic resistance, reversal drives, and immunizing reversal drives. While predictions about efficacy of these mechanisms have been optimistic, we lack detailed analyses of their expected dynamics. We develop a discrete time model for population genetics of a drive and proposed genetic countermeasures. Efficacy of drive reversal varies between countermeasures. For some parameter values, the model predicts unexpected behavior including polymorphic equilibria and oscillatory dynamics. The timing and number of released individuals containing a genetic countermeasure can substantially impact outcomes. The choice among countermeasures by researchers and regulators will depend on specific goals and population parameters of target populations.

evolutionary biology↗

bioRxiv2017

Impact Of Sequencing Depth And Read Length On Single Cell RNA Sequencing Data: Lessons From T Cells

Single cell RNA sequencing (scRNA-seq) has shown great potential in measuring the gene expression profiles of heterogeneous cell populations. In immunology, scRNA-seq allowed the characterisation of transcript sequence diversity of functionally relevant sub-populations of T cells, and notably the identification of the full length T cell receptor (TCR{beta}), which defines the specificity against cognate antigens. Several factors, such as RNA library capture, cell quality, and sequencing output have been suggested to affect the quality of scRNA-seq data, but these factors have not been systematically examined.\n\nWe studied the effect of read length and sequencing depth on the quality of gene expression profiles, cell type identification, and TCR{beta} reconstruction, utilising 1,305 publically available scRNA-seq datasets, and simulation-based analyses. Gene expression was characterised by an increased number of unique genes identified with short read lengths (<50 bp), but these featured higher technical variability compared to profiles from longer reads. TCR{beta} were detected in 1,027 cells (79%), with a success rate between 81% and 100% for datasets with at least 250,000 (PE) reads of length >50 bp.\n\nSufficient read length and sequencing depth can control technical noise to enable accurate identification of TCR{beta} and gene expression profiles from scRNA-seq data of T cells.

bioinformatics↗