scholarly journals Modeling confinement and reversibility of threshold-dependent gene drive systems in spatially-explicit Aedes aegypti populations

2019 ◽  
Author(s):  
Héctor M. Sánchez C. ◽  
Jared B. Bennett ◽  
Sean L. Wu ◽  
Gordana Rašić ◽  
Omar S. Akbari ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Disease Transmission ◽  
Release Site ◽  
Field Trials ◽  
Mosquito Vector ◽  
Gene Drive ◽  
Isolated Populations ◽  
Dependent Behavior ◽  
Wide Scale ◽  
Drive Systems

AbstractBackgroundThe discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently-engineered threshold-dependent gene drive systems - reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UDMEL - to explore their ability to be confined and remediated.ResultsWe simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UDMEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely.ConclusionsOur analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.

scholarly journals Antiviral Effectors and Gene Drive Strategies for Mosquito Population Suppression or Replacement to Mitigate Arbovirus Transmission by Aedes aegypti

Insects ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 52 ◽  
Author(s):  
Adeline Williams ◽  
Alexander Franz ◽  
William Reid ◽  
Ken Olson
Keyword(s):  
Aedes Aegypti ◽  
Disease Transmission ◽  
Mosquito Control ◽  
Control Strategies ◽  
Mosquito Vector ◽  
Close Monitoring ◽  
Gene Drive ◽  
Population Replacement ◽  
Effector Genes ◽  
Population Suppression

The mosquito vector Aedes aegypti transmits arthropod-borne viruses (arboviruses) of medical importance, including Zika, dengue, and yellow fever viruses. Controlling mosquito populations remains the method of choice to prevent disease transmission. Novel mosquito control strategies based on genetically manipulating mosquitoes are being developed as additional tools to combat arbovirus transmission. Genetic control of mosquitoes includes two basic strategies: population suppression and population replacement. The former aims to eliminate mosquito populations while the latter aims to replace wild populations with engineered, pathogen-resistant mosquitoes. In this review, we outline suppression strategies being applied in the field, as well as current antiviral effector genes that have been characterized and expressed in transgenic Ae. aegypti for population replacement. We discuss cutting-edge gene drive technologies that can be used to enhance the inheritance of effector genes, while highlighting the challenges and opportunities associated with gene drives. Finally, we present currently available models that can estimate mosquito release numbers and time to transgene fixation for several gene drive systems. Based on the recent advances in genetic engineering, we anticipate that antiviral transgenic Ae. aegypti exhibiting gene drive will soon emerge; however, close monitoring in simulated field conditions will be required to demonstrate the efficacy and utility of such transgenic mosquitoes.

scholarly journals Development of a confinable gene drive system in the human disease vector Aedes aegypti

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ming Li ◽  
Ting Yang ◽  
Nikolay P Kandul ◽  
Michelle Bui ◽  
Stephanie Gamez ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Field Trials ◽  
Pathogen Transmission ◽  
Control Measures ◽  
Mosquito Vector ◽  
Gene Drive ◽  
Wild Populations ◽  
Linked Gene ◽  
Pathogen Effector ◽  
Gene Drives

Aedes aegypti is the principal mosquito vector for many arboviruses that increasingly infect millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has sparked significant enthusiasm for genetic control of mosquitoes; however, no such system has been developed in Ae. aegypti. To fill this void, here we develop several CRISPR-based split gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, mathematical models predict that these systems could spread anti-pathogen effector genes into wild populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effector-linked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission.

scholarly journals MGDrivE 2: A simulation framework for gene drive systems incorporating seasonality and epidemiological dynamics

2020 ◽  
Author(s):  
Sean L. Wu ◽  
Jared B. Bennett ◽  
Héctor M. Sánchez C. ◽  
Andrew J. Dolgert ◽  
Tomás M. León ◽  
...  
Keyword(s):  
Population Dynamics ◽  
Disease Transmission ◽  
Field Trials ◽  
Pathogen Transmission ◽  
Environmental Data ◽  
List Type ◽  
Gene Drive ◽  
Simulation Framework ◽  
Implementation Framework ◽  
Drive Systems

AbstractInterest in gene drive technology has continued to grow as promising new drive systems have been developed in the lab and discussions are moving towards implementing field trials. The prospect of field trials requires models that incorporate a significant degree of ecological detail, including parameters that change over time in response to environmental data such as temperature and rainfall, leading to seasonal patterns in mosquito population density. Epidemiological outcomes are also of growing importance, as: i) the suitability of a gene drive construct for release will depend on its expected impact on disease transmission, and ii) initial field trials are expected to have a measured entomological outcome and a modeled epidemiological outcome.We present MGDrivE 2 (Mosquito Gene Drive Explorer 2): an extension of and development from the MGDrivE 1 simulation framework that investigates the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. Key strengths and improvements of the MGDrivE 2 framework are: i) the ability of parameters to vary with time and induce seasonal population dynamics, ii) an epidemiological module accommodating reciprocal pathogen transmission between humans and mosquitoes, and iii) an implementation framework based on stochastic Petri nets that enables efficient model formulation and flexible implementation.Example MGDrivE 2 simulations are presented to demonstrate the application of the framework to a CRISPR-based homing gene drive system intended to drive a disease-refractory gene into a population, incorporating time-varying temperature and rainfall data, and predict impact on human disease incidence and prevalence. Further documentation and use examples are provided in vignettes at the project’s CRAN repository.MGDrivE 2 is an open-source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling gene drive constructs as they move closer to field application and to infer their expected impact on disease transmission.

scholarly journals Using Gene Drive Technologies to Control Vector-Borne Infectious Diseases

2018 ◽  
Vol 10 (12) ◽  
pp. 4789 ◽  
Author(s):  
Stephanie James ◽  
Karen Tountas
Keyword(s):  
Disease Transmission ◽  
Sub Saharan Africa ◽  
Reproductive Capacity ◽  
World Health ◽  
Mosquito Vector ◽  
Gene Drive ◽  
African Region ◽  
Safety Testing ◽  
Malaria Burden ◽  
Health Organization

After years of success in reducing the global malaria burden, the World Health Organization (WHO) recently reported that progress has stalled. Over 90% of malaria deaths world-wide occurred in the WHO African Region. New tools are needed to regain momentum and further decrease the burden of malaria. Gene drive, an emerging technology that can enhance the inheritance of beneficial genes, offers potentially transformative solutions for overcoming these challenges. Gene drives may decrease disease transmission by interfering with the growth of the malaria parasite in the mosquito vector or reducing mosquito reproductive capacity. Like other emerging technologies, development of gene drive products faces technical and non-technical challenges and uncertainties. In 2018, to begin addressing such challenges, a multidisciplinary group of international experts published comprehensive recommendations for responsible testing and implementation of gene drive-modified mosquitoes to combat malaria in Sub-Saharan Africa. Considering requirements for containment, efficacy and safety testing, monitoring, stakeholder engagement and authorization, as well as policy and regulatory issues, the group concluded that gene drive products for malaria can be tested safely and ethically, but that this will require substantial coordination, planning, and capacity development. The group emphasized the importance of co-development and co-ownership of products by in-country scientists.

Detection of Fluorescent Powders and Their Effect on Survival and Recapture of Aedes aegypti (Diptera: Culicidae)

2019 ◽  
Vol 57 (1) ◽  
pp. 266-272 ◽  
Author(s):  
Diana Rojas-Araya ◽  
Barry W Alto ◽  
Nathan Burkett-Cadena ◽  
Derek At Cummings
Keyword(s):  
Aedes Aegypti ◽  
Disease Transmission ◽  
Adult Survival ◽  
Mosquito Vector ◽  
Host Seeking ◽  
Baited Traps ◽  
Impact On Survival ◽  
Invasive Mosquito ◽  
Risk Of Disease ◽  
Potential Impact

Abstract The use of insect markers, such as fluorescent powders, is a useful tool for studying ecological and epidemiological questions. Evaluating their effect on vectors of human disease agents, such as the invasive mosquito vector Aedes aegypti (Linnaeus), is crucial for their practical and reliable use, especially in parameters linked to the risk of disease transmission such as adult survival, dispersal, and host-seeking. Seven fluorescent powders (Hercules Radiant, DayGlo (DG), Risk Reactor (RR), and Angstrom Technologies), applied externally on cohorts of Ae. aegypti female mosquitoes, were tested to determine their impact on survival and recapture by baited mosquito traps, and their detectability after being exposed to controlled laboratory and semifield environments. There were no significant differences in survival among marked and unmarked females across all powders. Marked females were significantly less likely to be captured in baited traps relative to unmarked females, except for one of the DG powders. All females remained visibly marked on five parts of their body for 30 d (under both environments), except for one of the RR powders. The tested powders and application method are suitable for tracking mosquitoes throughout most of their lives under different environments, without significantly affecting their survival, but with potential impact on recapture by baited traps, possibly due to effects on senses or other physiological traits.

scholarly journals Genomic insertion locus and Cas9 expression in the germline affect CRISPR/Cas9-based gene drive performance in the yellow fever mosquito Aedes aegypti

2021 ◽  
Author(s):  
William R Reid ◽  
Jingyi Lin ◽  
Adeline E Williams ◽  
Rucsanda Juncu ◽  
Ken E Olson ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Yellow Fever ◽  
Drive System ◽  
Gene Drive ◽  
Yellow Fever Mosquito ◽  
Genomic Locus ◽  
Population Replacement ◽  
Novel Approach ◽  
Drive Systems ◽  
Insertion Locus

The yellow fever mosquito Aedes aegypti is a major vector of arthropod-borne viruses, including dengue, chikungunya, and Zika. A novel approach to mitigate arboviral infections is to generate mosquitoes refractory to infection by overexpressing antiviral effector molecules. Such an approach requires a mechanism to spread these antiviral effectors through a population, for example, by using CRISPR/Cas9-based gene drive systems. Here we report an autonomous single-component gene drive system in Ae. aegypti that is designed for persistent population replacement. Critical to the design of a single-locus autonomous gene drive is that the selected genomic locus be amenable to both gene drive and the appropriate expression of the antiviral effector. In our study, we took a reverse engineering approach to target two genomic loci ideal for the expression of antiviral effectors and further investigated the use of three promoters for Cas9 expression (nanos, β2-tubulin, or zpg) for the gene drive. We found that both promoter selection and genomic target site strongly influenced the efficiency of the drive, resulting in 100% inheritance in some crosses. We also observed the formation of inheritable gene drive blocking indels (GDBI) in the genomic locus with the highest levels of gene drive. Overall, our drive system forms a platform for the further testing of driving antipathogen effector genes through Ae. aegypti populations.

scholarly journals Digital droplet PCR and IDAA for the detection of CRISPR indel edits in the malaria species Anopheles stephensi

BioTechniques ◽  
2020 ◽  
Vol 68 (4) ◽  
pp. 172-179 ◽  
Author(s):  
Rebeca Carballar-Lejarazú ◽  
Adam Kelsey ◽  
Thai Binh Pham ◽  
Eric P Bennett ◽  
Anthony A James
Keyword(s):  
Anopheles Stephensi ◽  
Field Testing ◽  
Nonhomologous End Joining ◽  
Mosquito Vector ◽  
Gene Drive ◽  
End Joining ◽  
Indel Detection ◽  
Vector Mosquito ◽  
Droplet Pcr ◽  
Drive Systems

CRISPR/Cas9 technology is a powerful tool for the design of gene-drive systems to control and/or modify mosquito vector populations; however, CRISPR/Cas9-mediated nonhomologous end joining mutations can have an important impact on generating alleles resistant to the drive and thus on drive efficiency. We demonstrate and compare the insertions or deletions (indels) detection capabilities of two techniques in the malaria vector mosquito Anopheles stephensi: Indel Detection by Amplicon Analysis (IDAA™) and Droplet Digital™ PCR (ddPCR™). Both techniques showed accuracy and reproducibility for indel frequencies across mosquito samples containing different ratios of indels of various sizes. Moreover, these techniques have advantages that make them potentially better suited for high-throughput nonhomologous end joining analysis in cage trials and contained field testing of gene-drive mosquitoes.

scholarly journals Silencing of end-joining repair for efficient site-specific gene insertion after TALEN/CRISPR mutagenesis in Aedes aegypti

2015 ◽  
Vol 112 (13) ◽  
pp. 4038-4043 ◽  
Author(s):  
Sanjay Basu ◽  
Azadeh Aryan ◽  
Justin M. Overcash ◽  
Glady Hazitha Samuel ◽  
Michelle A. E. Anderson ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Specific Gene ◽  
Gene Drive ◽  
Transcription Activator ◽  
End Joining ◽  
Site Specific ◽  
Gene Insertion ◽  
Guide Rnas ◽  
Essential Components ◽  
Drive Systems

Conventional control strategies for mosquito-borne pathogens such as malaria and dengue are now being complemented by the development of transgenic mosquito strains reprogrammed to generate beneficial phenotypes such as conditional sterility or pathogen resistance. The widespread success of site-specific nucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 in model organisms also suggests that reprogrammable gene drive systems based on these nucleases may be capable of spreading such beneficial phenotypes in wild mosquito populations. Using the mosquito Aedes aegypti, we determined that mutations in the FokI domain used in TALENs to generate obligate heterodimeric complexes substantially and significantly reduce gene editing rates. We found that CRISPR/Cas9-based editing in the mosquito Ae. aegypti is also highly variable, with the majority of guide RNAs unable to generate detectable editing. By first evaluating candidate guide RNAs using a transient embryo assay, we were able to rapidly identify highly effective guide RNAs; focusing germ line-based experiments only on this cohort resulted in consistently high editing rates of 24–90%. Microinjection of double-stranded RNAs targeting ku70 or lig4, both essential components of the end-joining response, increased recombination-based repair in early embryos as determined by plasmid-based reporters. RNAi-based suppression of Ku70 concurrent with embryonic microinjection of site-specific nucleases yielded consistent gene insertion frequencies of 2–3%, similar to traditional transposon- or ΦC31-based integration methods but without the requirement for an initial docking step. These studies should greatly accelerate investigations into mosquito biology, streamline development of transgenic strains for field releases, and simplify the evaluation of novel Cas9-based gene drive systems.

scholarly journals Assessing connectivity despite high diversity in island populations of a malaria mosquito

2018 ◽  
Author(s):  
Christina M. Bergey ◽  
Martin Lukindu ◽  
Rachel M. Wiltshire ◽  
Michael C. Fontaine ◽  
Jonathan K. Kayondo ◽  
...  
Keyword(s):  
Lake Victoria ◽  
Field Testing ◽  
Accurate Estimation ◽  
Gene Drive ◽  
Classical Analysis ◽  
Isolated Populations ◽  
Island Populations ◽  
Polymorphic Species ◽  
Drive Systems ◽  
Shared Variation

AbstractDocumenting isolation is notoriously difficult for species with vast polymorphic populations. High proportions of shared variation impede estimation of connectivity, even despite leveraging information from many genetic markers. We overcome these impediments by combining classical analysis of neutral variation with assays of the structure of selected variation, demonstrated using populations of the principal African malaria vector Anopheles gambiae. Accurate estimation of mosquito migration is crucial for efforts to combat malaria. Modeling and cage experiments suggest that mosquito gene drive systems will enable malaria eradication, but establishing safety and efficacy requires identification of isolated populations in which to conduct field-testing. We assess Lake Victoria islands as candidate sites, finding one island 30 kilometers offshore is as differentiated from mainland samples as populations from across the continent. Collectively, our results suggest sufficient contemporary isolation of these islands to warrant consideration as field-testing locations and illustrate shared adaptive variation as a useful proxy for connectivity in highly polymorphic species.

scholarly journals PENGENDALIAN VEKTOR NYAMUK AEDES AEGYPTI DI RUMAH SAKIT KOTA SURABAYA

2019 ◽  
Vol 13 (1) ◽  
pp. 73
Author(s):  
Ekalina Atikasari ◽  
Lilis Sulistyorini
Keyword(s):  
Aedes Aegypti ◽  
Vector Control ◽  
Environmental Health ◽  
Disease Transmission ◽  
Mosquito Control ◽  
Secondary Data ◽  
Mosquito Vector ◽  
Human Contact ◽  
The Republic ◽  
And Control

Vector control is an approach using the basic principles of management and consideration of disease transmission and control. The purpose of vector control is to reduce vector breeding habitats, reduce vector density, inhibit disease transmission, reduce human contact with vectors so that vector-borne disease transmission can be controlled more rationally, effectively and efficiently. This study aims to analyze the effectiveness of Aedes aegypti mosquito control vector in a hospital in Surabaya. The Control carried out by the Hospital is to eradicate Aedes aegypti mosquitoes by installing Ovitrap, Thermal Fogging, Cold Fogging and Spraying. The type of analysis used is descriptive observational. Data collection was carried out in February of 2017 at K3 unit and Environmental Health of Surabaya Hospital. The data used are hospital pest and rodent control report, secondary data aboutnumber of mosquito, number of larvae and number of Aedes aegypti mosquito eggs obtained from unit of K3 and Environmental Health. The conclusions for the hospital are: (1) always report the Aedes aegypti mosquito vector routine every months; (2) eradicating mosquitoes in difficult places such as patient and dense populated areas; (3) based on Regulation of the Minister of Health of the Republic of Indonesia Number 374 / MENKES / PER / III / 2010 concerning Vector Control four of the six tools used in the Hospital have been used

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