Biology subjects

Childs, L. M.

Publications and source records attributed to Childs, L. M..

10 recordsLinked to original sources

bioRxiv2026

Modeling population control via tunable sex ratio distorter gene drives in Aedes aegypti

Aedes aegypti, a major vector of arboviruses, belong to subfamily Culicinae, a diverse group of mosquitoes with homomorphic sex-determining chromosomes. Males are the heterogametic sex with a dominant male-determining locus (M locus). The M locus and its counterpart m locus are embedded in a region of suppressed recombination, with a large portion of this recombination desert showing significant molecular differentiation despite homomorphy. We developed a mathematical framework to examine M-linked genome editors that specifically target the m-chromosome during spermatogenesis, mimicking the naturally occurring sex ratio distorters (SRDs) in Culicinae that produce male-biased meiotic drives. Unlike previous models for species with heteromorphic sex chromosomes (e.g., X and Y), we incorporate features stemming from the homomorphic nature of the Ae. aegypti sex chromosomes such as varied linkage to the M locus, making the degree of super-Mendelian inheritance readily tunable. We evaluated in silico SRDs with a range of M-linkage and editing efficiencies and established the theoretical foundation for developing highly efficient SRDs that outperform several methods of population suppression. These SRDs can be tuned to mitigate impact on a neighboring population. The framework developed here is suitable for exploring SRD-mediated genetic biocontrol of numerous pest species with homomorphic sex chromosomes.

genetics↗

bioRxiv2025

Paying upfront: successful initial infections protect against severe future infections

Understanding the consistency with which individual hosts respond to repeated pathogen exposures is crucial for accurately modeling pathogen transmission and eco-evolutionary dynamics. When hosts face repeated pathogen exposures, immune memory is expected to reduce the probability and/or severity of subsequent infections, yet it remains unclear whether individuals remain consistent in their level of response relative to others. We investigated this question in house finches (Haemorhous mexicanus) from two populations varying in history of endemism of the bacterial pathogen Mycoplasma gallisepticum (MG). Individuals were confirmed to be MG-naive at capture and then experimentally inoculated twice with MG, allowing recovery between inoculations. We then asked if host responses to the second inoculation were predicted by responses to initial inoculation, sex, or population of origin. Our results suggest that individuals were not consistent in their relative response levels; rather, a successful initial infection provided protection against a severe second infection, increasing both tolerance and resistance. While we found no population differences in response to the second inoculation, males showed higher susceptibility to the second inoculation than females. Investigating and accounting for individual variation in response to subsequent exposures may improve the precision and accuracy of transmission models for wildlife pathogens.

ecology↗

bioRxiv2025

Larval environment reshapes mosquito disease risk via phenotypic and molecular plasticity

Early-life environmental conditions can exert profound, lasting effects on adult phenotypes, with major consequences for fitness and disease transmission, especially in holometabolous insects like mosquitoes, which are a key vector species. Yet, the molecular mechanisms through which juvenile environments shape adult physiology and behavior via transstadial effects remain largely unresolved. Here, we demonstrate that larval competition, a key ecological stressor, profoundly alters adult body size, survival, reproductive output, host-seeking behavior, olfactory neurophysiology, and vector competence in the mosquito Aedes aegypti. Crucially, using transcriptomic profiling and integrative network analyses, we identify seven regulatory hub genes whose expression is strongly associated with size-dependent variation in olfactory behavior, reproductive investment, and Zika virus transmission potential. These hub genes belong to gene modules enriched for functions in chemosensory processing, metabolic regulation, and signal transduction, revealing a molecular framework mediating environmentally induced plasticity across metamorphosis. Integrating these empirical findings into a transmission model, we show that incomplete larval control can inadvertently increase outbreak risk by producing larger, longer-lived, and more competent vectors. Our results uncover molecular mechanisms underpinning phenotypic plasticity in disease vectors and highlight the critical need to account for transstadial effects in models of vector-borne disease transmission.

physiology↗

bioRxiv2025

Immunity can impose a reproduction-survival tradeoff on human malaria parasites

Many pathogenic organisms produce specialized life stages for within-host multiplication versus on-ward transmission, including malaria parasites. Traits that enable faster multiplication--including limited investment into transmission stage production--should put host health at greater risk (all else equal). Yet it is not clear why parasites do not evolve ever faster multiplication rates, since malaria parasites do not appear to adhere to tradeoffs between the rate and duration of transmission that are classically predicted to constrain parasite evolution. To address this puzzle, we introduce an age-of-infection structured within-host mathematical model incorporating dynamic immune clearance to investigate potential tradeoffs and understand how parasites optimize their transmission investment. When investment is constant across all ages of infection, increased transmission investment reduces infection duration and parasite fitness, with optimal investment occurring at a relatively low value (around 5%), far lower than the optimum recovered from models that lack dynamic feedbacks between parasite investment and immune clearance. For age-varying strategies, our model shows that malaria parasites can enhance their fitness by delaying transmission investment to allow for faster within-host multiplication initially. Our results indicate that adaptive immunity can impose a survival-reproduction tradeoff that explains why malaria parasites cannot evolve ever faster within-host multiplication. Our theoretical framework provides a basis for understanding how transmission investment strategies alter the timing of infectiousness over the lifespan of malaria infections, with implications for parasite evolution in response to control efforts.

evolutionary biology↗

bioRxiv2024

Prior exposure to pathogens augments host heterogeneity in susceptibility and has key epidemiological consequences

Pathogen epidemics are key threats to human and wildlife health. Across systems, host protection from pathogens following initial exposure is often incomplete, resulting in recurrent epidemics through partially-immune hosts. Variation in population-level protection has important consequences for epidemic dynamics, but how acquired protection influences inter{-}individual heterogeneity in susceptibility and its epidemiological consequences remains understudied. We experimentally investigated whether prior exposure (none, low-dose, or high{-}dose) to a bacterial pathogen alters host heterogeneity in susceptibility among songbirds. Hosts with no prior pathogen exposure had little variation in protection, but heterogeneity in susceptibility was significantly augmented by prior pathogen exposure, with the highest variability detected in hosts given high-dose prior exposure. An epidemiological model parameterized with experimental data found that heterogeneity in susceptibility from prior exposure more than halved epidemic sizes compared with a homogeneous population with identical mean protection. However, because infection-induced mortality was also greatly reduced in hosts with prior pathogen exposure, reductions in epidemic size were smaller than expected in hosts with prior exposure. These results highlight the importance of variable protection from prior exposure and/or vaccination in driving population-level heterogeneity and epidemiological dynamics.

microbiology↗

bioRxiv2024

Developmental synchrony and extraordinary multiplication rates in pathogenic organisms

The multiplication rates of pathogenic organisms influence disease progression, efficacy of immunity and therapeutics, and potential for within-host evolution. Thus, accurate estimates of multiplication rates are essential for biological understanding. We recently showed that common methods for inferring multiplication rates from malaria infection data substantially overestimate true values (i.e., under simulated scenarios), providing context for extraordinarily large estimates in human malaria parasites. A key unknown is whether this bias arises specifically from malaria parasite biology or represents a broader concern. Here we identify the potential for biased multiplication rate estimates across pathogenic organisms with different developmental biology by generalizing a within-host malaria model. We find that diverse patterns of developmental sampling bias--the change in detectability over developmental age--reliably generate overestimates of the fold change in abundance, obscuring not just true growth rates but potentially even whether populations are expanding or declining. This pattern emerges whenever synchrony, the degree to which development is synchronized across the population of pathogenic organisms comprising an infection, decays with time. Only with simulated increases in synchrony do we find noticeable underestimates of multiplication rates. Obtaining robust estimates of multiplication rates may require accounting for diverse patterns of synchrony in pathogenic organisms. Subjectscomputational biology, theoretical biology, ecology, developmental biology

ecology↗

bioRxiv2022

Eos promotes TH2 differentiation by propagating the IL-2/STAT5 signaling pathway.

The Ikaros zinc finger transcription factor Eos has been commonly implicated in regulatory T cells to promote their immunosuppressive functions. Paradoxically, a new role is emerging for Eos in promoting pro-inflammatory responses of conventional CD4+ T cells in the dysregulated setting of autoimmunity. Even so, the precise role of Eos in regulating the differentiation and function of healthy effector CD4+ T cell subsets remains unclear. Here, we find that Eos is a positive regulator of CD4+ T helper 2 (TH2) cells--effector T cells implicated in the induction of allergic asthma. Using murine in vitro TH2 cells and an in vivo house dust mite asthma model, we found that Eos-deficient T cells had reduced expression of key TH2 transcription factors, effector cytokines, and differentiation receptors. Mechanistically, among various TH2-polarizing pathways, the IL-2/STAT5 axis and its downstream TH2 gene targets emerged as one of the most significantly downregulated networks in Eos deficiency. Using in vitro TH2 cells and overexpression of Eos zinc-finger-domain mutants, we discovered that Eos forms a novel complex with and supports the tyrosine-phosphorylated signaling activity of STAT5. Overall, these data define a novel regulatory mechanism whereby Eos promotes IL-2/STAT5 activity to facilitate TH2 differentiation.

immunology↗

bioRxiv2021

Accounting for heterogeneity in wild adult samples to measure insecticide resistance in Anopheles malaria vectors

BackgroundSystematic, long-term, and spatially representative monitoring of insecticide resistance in mosquito populations is urgently needed to quantify its impact on malaria transmission, and to combat failing interventions when resistance emerges. Resistance assays on wild-caught adult mosquitoes (known as adult-capture) offer an alternative to the current protocols, and can be done cheaply, in a shorter time frame, and in the absence of an insectary. However, quantitative assessments of the performance of these assays relative to the gold standard, which involves rearing larvae in an insectary, are lacking. Methodology/Principal findingsWe developed a discrete-time deterministic mosquito lifecycle model to simulate insecticide resistance assays from adult-captured mosquito collection in a heterogeneous environment compared to the gold standard larval capture methods, and to quantify possible biases in the results. We incorporated non-lethal effects of insecticide exposure that have been demonstrated in laboratory experiments, spatial structure, and the impact of multiple exposure to insecticides and natural ageing on mosquito death rates during the assay. Using output from this model, we compared the results of these assays to true resistance as measured by the presence of the resistance allele. In simulated samples of 100 test mosquitoes, reflecting WHO-recommended sample sizes, we found that compared to adult-captured assays (MSE = 0.0059), larval-captured assays were a better measure of true resistance (MSE = 0.0018). Using a correction model, we were able to improve the accuracy of the adult-captured assay results (MSE = 0.0038). Bias in the adult-capture assays was dependent on the level of insecticide resistance rather than coverage of bed nets or spatial structure. Conclusions/SignificanceUsing adult-captured mosquitoes for resistance assays has logistical advantages over the standard larval-capture collection, and may be a more accurate sample of the mosquito population. These results show that adult-captured assays can be improved using a simple mathematical approach and used to inform resistance monitoring programs. Author SummaryGrowing insecticide resistance in the mosquitoes that transmit malaria necessitates more widespread monitoring. Conducting assays on mosquitoes captured as adults is logistically simpler than raising them from eggs or larvae, the current recommended practice. However, this method is not widely used because survival when exposed to insecticide is known to depend on age and history of previous history as well as genetic resistance-factors that cannot be controlled when testing wild-caught adults. Here, we developed a mathematical model to quantify the difference in resistance measured via adult-capture assays compared to the gold standard larval-capture assays. We find that adult-capture assay results can be easily corrected using a formula based only on the measured resistance. This result has the potential to expand access to monitoring by reducing the time and infrastructure required to conduct these tests.

evolutionary biology↗

bioRxiv2021

Modeling the effects of Aedes aegypti's larval environment on adult body mass at emergence

Mosquitoes vector harmful pathogens that infect millions of people every year, and developing approaches to effectively control mosquitoes is a topic of great interest. However, the success of many control measures is highly dependent upon ecological, physiological, and life history traits of the mosquito species. The behavior of mosquitoes and their potential to vector pathogens can also be impacted by these traits. One trait of interest is mosquito body mass, which depends upon many factors associated with the environment in which juvenile mosquitoes develop. Our experiments examined the impact of larval density on the body mass of Aedes aegypti mosquitoes, which are important vectors of dengue, Zika, yellow fever, and other pathogens. To investigate the interactions between the larval environment and mosquito body mass, we built a discrete time mathematical model that incorporates body mass, larval density, and food availability and fit the model to our experimental data. We considered three categories of model complexity informed by data, and selected the best model within each category using Akaikes Information Criterion. We found that the larval environment is an important determinant of the body mass of mosquitoes upon emergence. Furthermore, we found that larval density has greater impact on body mass of adults at emergence than on development time, and that inclusion of density dependence in the survival of female aquatic stages in models is important. We discuss the implications of our results for the control of Aedes mosquitoes and on their potential to spread disease. Author summaryIn this work we examined how the environment in which young mosquitoes develop affects their adult body size as measured by adult body mass. Adult size has potential impacts on mosquito behavior and the ability of mosquitoes to transmit disease. We used a combination of experimental work and mathematical modeling to determine important factors affecting adult mosquito body size. In our model, we incorporated potentially interacting aspects of the mosquito life cycle and traits that affect mosquito growth as juveniles. These aspects include body mass, density of the population, and level of available resource. We compared different models to determine the one that best describes the data. As mass at emergence is linked to the success of adult mosquitoes to produce offspring and to their ability transmit pathogens, we discuss how important influences on development and survival of young mosquitoes affect mosquito control and disease spread.

ecology↗

bioRxiv2020

Current estimates of malaria basic reproduction number underestimate parasite transmission efficiency due to multiple blood feeding

Many mosquito species, including the major malaria vector Anopheles gambiae, naturally undergo multiple reproductive cycles of blood feeding, egg development and egg laying in their lifespan. Such complex mosquito behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. Here, we examine how Plasmodium falciparum development and transmission potential is impacted when infected mosquitoes feed an additional time. We measured P. falciparum oocyst size and performed sporozoite time course analyses to determine the parasite’s extrinsic incubation period (EIP), i.e. the time required by parasites to reach infectious sporozoite stages, in An. gambiae females blood fed either once or twice. An additional blood feed at 3 days post infection drastically accelerates oocyst growth rates, causing earlier sporozoite accumulation in the salivary glands, thereby shortening the EIP (reduction of 2.25 ± 0.39 days). Moreover, parasite growth is further accelerated in transgenic mosquitoes with reduced reproductive capacity, which mimic genetic modifications currently proposed in population suppression gene drives. We incorporate our shortened EIP values into a measure of transmission potential, the basic reproduction number R0, and find the average R0 is remarkably higher (range: 10.1%–12.1% increase) across sub-Saharan Africa than when using traditional EIP measurements. These data suggest that malaria elimination may be substantially more challenging and that younger mosquitoes or those with reduced reproductive ability may provide a larger contribution to infection than currently believed. Our findings have profound implications for current and future mosquito control interventions.Significance Statement In natural settings the female Anopheles gambiae mosquito, the major malaria vector, blood feeds multiple times in her lifespan. Here we demonstrate that an additional blood feed accelerates the growth of Plasmodium falciparum malaria parasites in this mosquito. Incorporating these data into a mathematical model across sub-Saharan Africa reveals that malaria transmission potential is likely to be substantially higher than previously thought, making disease elimination more difficult. Additionally, we show that control strategies that manipulate mosquito reproduction with the aim of suppressing Anopheles populations may inadvertently favor malaria transmission. Our data also suggest that parasites can be transmitted by younger mosquitoes, which are less susceptible to insecticide killing, with negative implications for the success of insecticide-based strategies.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗