Nikolai Windbichler's research while affiliated with Imperial College London and other places

Publications (132)

Article
Full-text available
Key behaviours, physiologies and gene expressions in Anopheles mosquitoes impact the transmission of Plasmodium. Such mosquito factors are rhythmic to closely follow diel rhythms. Here, we set to explore the impact of the mosquito circadian rhythm on the tripartite interaction between the vector, the parasite and the midgut microbiota, and investig...
Article
Gene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptid...
Article
Full-text available
Background Gene drives are a genetic engineering method where a suite of genes is inherited at higher than Mendelian rates and has been proposed as a promising new vector control strategy to reinvigorate the fight against malaria in sub-Saharan Africa. Methods Using an agent-based model of malaria transmission with vector genetics, the impacts of...
Article
Full-text available
Gene drives for mosquito population modification are novel tools for malaria control. Strategies to safely test antimalarial effectors in the field are required. Here, we modified the Anopheles gambiae zpg locus to host a CRISPR/Cas9 integral gene drive allele ( zpg D ) and characterized its behaviour and resistance profile. We found that zpg D dom...
Article
Full-text available
Gene drives are promising tools for the genetic control of insect vector or pest populations. CRISPR-based gene drives are generally highly complex synthetic constructs consisting of multiple transgenes and their respective regulatory elements. This complicates the generation of new gene drives and the testing of the behavior of their constituent f...
Preprint
Full-text available
Gene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptid...
Article
Full-text available
Genetically modified (GM) mosquitoes expressing anti-plasmodial effectors propagating through wild mosquito populations by means of gene drive is a promising tool to support current malaria control strategies. The process of generating GM mosquitoes involves genetic transformation of mosquitoes from a laboratory colony and, often, interbreeding wit...
Preprint
Full-text available
Genetically engineering mosquitoes is a promising new vector control strategy to reinvigorate the fight against malaria in Sub-Saharan Africa. Using an agent-based model of malaria transmission with vector genetics, we examine the impacts of releasing population-replacement gene drive mosquitoes on malaria transmission and quantify the gene drive s...
Preprint
Full-text available
Genetically modified (GM) mosquitoes expressing anti-plasmodial effectors propagating through wild mosquito populations by means of gene drive is a promising tool to support current malaria control strategies. The process of generating GM mosquitoes involves genetic transformation of mosquitoes from a laboratory colony and, often, interbreeding wit...
Article
Full-text available
Background Genetic sex ratio distorters are systems aimed at effecting a bias in the reproductive sex ratio of a population and could be applied for the area-wide control of sexually reproducing insects that vector disease or disrupt agricultural production. One example of such a system leading to male bias is X-shredding, an approach that interfer...
Article
Full-text available
Gene drives for mosquito population replacement are promising tools for malaria control. However, there is currently no clear pathway for safely testing such tools in endemic countries. The lack of well-characterized promoters for infection-relevant tissues and regulatory hurdles are further obstacles for their design and use. Here we explore how m...
Article
Full-text available
Malaria parasites develop as oocysts in the mosquito for several days before they are able to infect a human host. During this time, mosquitoes take bloodmeals to replenish their nutrient and energy reserves needed for flight and reproduction. We hypothesized that these bloodmeals are critical for oocyst growth and that experimental infection proto...
Preprint
Full-text available
Malaria parasites develop as oocysts in the mosquito for several days before they are able to infect a human host. During this time, mosquitoes take regular bloodmeals to replenish their nutrient and energy reserves needed for flight and reproduction. We hypothesized that these bloodmeals are critical for oocyst growth and that experimental infecti...
Article
Full-text available
Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistan...
Article
Full-text available
Vector control has been a key component in the fight against malaria for decades, and chemical insecticides are critical to the success of vector control programs worldwide. However, increasing resistance to insecticides threatens to undermine these efforts. Understanding the evolution and propagation of resistance is thus imperative to mitigating...
Preprint
Full-text available
Genetic sex ratio distorters have potential for the area-wide control of harmful insect populations. Endonucleases targeting the X-chromosome and whose activity is restricted to male gametogenesis have recently been pioneered as a means to engineer such traits. Here we enabled endogenous CRISPR/Cas9 and CRISPR/Cas12a activity during spermatogenesis...
Preprint
Full-text available
Gene drives for mosquito population replacement are promising tools for malaria control. However, there is currently no clear pathway for safely testing such tools in endemic countries. The lack of well-characterized promoters for infection-relevant tissues and regulatory hurdles are further obstacles for their design and use. Here we explore how m...
Article
Full-text available
In cells, organs and whole organisms, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment¹. In many animals, nutrient sensors are found within the enteroendocrine cells of the digestive system; however, less is known about nutrient sensing in their cellular siblings, the absorptive enterocytes¹. Here we use...
Article
Full-text available
Synthetic sex distorters have recently been developed in the malaria mosquito, relying on endonucleases that target the X-chromosome during spermatogenesis. Although inspired by naturally-occurring traits, it has remained unclear how they function and, given their potential for genetic control, how portable this strategy is across species. We estab...
Preprint
Full-text available
Malaria parasites develop and grow as oocysts in the mosquito for several days before being able to infect another human. During this time, mosquitoes take regular bloodmeals to replenish their nutrient and energy reserves needed for flight and reproduction. We hypothesized that supplemental bloodmeals are critical for oocyst growth and that experi...
Preprint
Full-text available
Vector control has been a key component in the fight against malaria for decades, and chemical insecticides are critical to the success of vector control programs worldwide. However, increasing resistance to insecticides threatens to undermine these efforts. Understanding the evolution and propagation of resistance is thus imperative to mitigating...
Preprint
Full-text available
Synthetic sex distorters have recently been developed in the malaria mosquito, relying on endonucleases that target the X-chromosome during spermatogenesis. Although inspired by naturally-occurring traits, it has remained unclear how they function and, given their potential for genetic control, how portable this strategy is across species. We estab...
Article
Full-text available
Gene Drives are regarded as future tools with a high potential for population control. Due to their inherent ability to overcome the rules ofMendelian inheritance, gene drives (GD) may spread genes rapidly through populations of sexually reproducing organisms. A release of organisms carrying a GD would constitute a paradigm shift in the handling of...
Article
Making males in a fruit fly pest The Mediterranean fruit fly or Medfly ( Ceratitis capitata ) is a global and highly destructive fruit pest. Meccariello et al. identified the master gene for male sex determination on the Y chromosome of Medfly and named it Maleness-on-the-Y ( MoY ) (see the Perspective by Makki and Meller). Flies of each sex were t...
Preprint
Full-text available
In insects, rapidly evolving primary sex-determining signals are transduced by a conserved regulatory module producing sex-specific proteins that direct sexual differentiation1-4. In the agricultural pest Ceratitis capitata (medfly), a Y-linked Maleness factor (M) is thought to repress the autoregulatory splicing of transformer (Cctra), which is re...
Article
Full-text available
Background The development of malaria transmission-blocking strategies including the generation of malaria refractory mosquitoes to replace the wild populations through means of gene drives hold great promise. The standard membrane feeding assay (SMFA) that involves mosquito feeding on parasitized blood through an artificial membrane system is a vi...
Article
Full-text available
A first generation of CRISPR-based gene drives has now been tested in the laboratory in a number of organisms, including malaria vector mosquitoes. Challenges for their use in the area-wide genetic control of vector-borne disease have been identified, including the development of target site resistance, their long-term efficacy in the field, their...
Article
Full-text available
The ability to erect rationally-engineered reproductive barriers in animal or plant species promises to enable a number of biotechnological applications such as the creation of genetic firewalls, the containment of gene drives or novel population replacement and suppression strategies for genetic control. However, to date no experimental data exist...
Preprint
Full-text available
First generation CRISPR-based gene drives have now been tested in the laboratory in a number of organisms including malaria vector mosquitoes. A number of challenges for their use in the area-wide genetic control of vector-borne disease have been identified. These include the development of target site resistance, their long-term efficacy in the fi...
Preprint
Full-text available
The ability to erect rationally-engineered reproductive barriers in animal or plant species promises to enable a number of biotechnological applications such as the creation of genetic firewalls, the containment of gene drives or novel population replacement and suppression strategies for genetic control. However, to date no experimental data exist...
Article
Full-text available
CRISPR-based synthetic sex ratio distorters, which operate by shredding the X-chromosome during male meiosis, are promising tools for the area-wide control of harmful insect pest or disease vector species. X-shredders have been proposed as tools to suppress insect populations by biasing the sex ratio of the wild population toward males, thus reduci...
Preprint
Full-text available
CRISPR-based synthetic sex ratio distorters, that operate by shredding the X-chromosome during male meiosis, are promising tools for the area-wide control of harmful insect pest or disease vector species. However, the selection of gRNA targets, in the form of high-copy sequence repeats on the X chromosome of a given species, is difficult since such...
Article
Y chromosome function, structure and evolution is poorly understood in many species including the Anopheles genus of mosquitoes, an emerging model system for studying speciation that also represents the major vectors of malaria. While the Anopheline Y had previously been implicated in male mating behavior, recent data from the Anopheles gambiae com...
Article
Full-text available
Understanding how phenotypic differences between males and females arise from the sex-biased expression of nearly identical genomes can reveal important insights into the biology and evolution of a species. Among Anopheles mosquito species, these phenotypic differences include vectorial capacity, as it is only females that blood feed and thus trans...
Article
Full-text available
The retargeting of protein-DNA specificity, outside of extremely modular DNA binding proteins such as TAL effectors, has generally proved to be quite challenging. Here, we describe structural analyses of five different extensively retargeted variants of a single homing endonuclease, that have been shown to function efficiently in ex vivo and in viv...
Preprint
Full-text available
Y chromosome function, structure and evolution is poorly understood in many species including the Anopheles genus of mosquitoes, an emerging model system for studying speciation that also represents the major vectors of malaria. While the Anopheline Y had previously been implicated in male mating behavior, recent data from the Anopheles gambiae com...
Preprint
Full-text available
Understanding how phenotypic differences between males and females arise from the sex-biased expression of nearly identical genomes can often reveal important insights into the biology and evolution of a species. Among Anopheles mosquito species, these phenotypic differences include vectorial capacity, as it is only females that blood feed and thus...
Article
Full-text available
Genetic control aims to reduce the ability of insect pest populations to cause harm via the release of modified insects. One strategy is to bias the reproductive sex ratio towards males so that a population decreases in size or is eliminated altogether due to a lack of females. We have shown previously that sex ratio distortion can be generated syn...
Article
Full-text available
Significance Interest in male mosquitoes has been motivated by the potential to develop novel vector control strategies, exploiting the fact that males do not feed on blood or transmit diseases, such as malaria. However, genetic studies of male Anopheles mosquitoes have been impeded by the lack of molecular characterization of the Y chromosome. Her...
Article
Full-text available
Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP00...
Article
Full-text available
Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP00...
Article
Full-text available
The draft genome sequence of Italian specimens of the Asian tiger mosquito Aedes (Stegomyia) albopictus (Diptera: Culicidae) was determined using a standard NGS (next generation sequencing) approach. The size of the assembled genome is comparable to that of Aedes aegypti; the two mosquitoes are also similar as far as the high content of repetitive...
Article
Full-text available
Transgenesis is an essential tool to investigate gene function and to introduce desired characters in laboratory organisms. Setting up transgenesis in non-model organisms is challenging due to the diversity of biological life traits and to knowledge gaps in genomic information. Some procedures will be broadly applicable to many organisms, others ha...
Article
Full-text available
It has been theorized that inducing extreme reproductive sex ratios could be a method to suppress or eliminate pest populations. Limited knowledge about the genetic makeup and mode of action of naturally occurring sex distorters and the prevalence of co-evolving suppressors has hampered their use for control. Here we generate a synthetic sex distor...
Article
Significance Interfering with sex determination and male fertility are potentially powerful approaches for the genetic control of the human malaria vector Anopheles gambiae. Despite this fact, the male-specific Y chromosome of this mosquito has remained largely unexplored, because of its repetitive, heterochromatic structure. Little is known about...
Article
Full-text available
Selfish genes are DNA elements that increase their rate of genetic transmission at the expense of other genes in the genome and can therefore quickly spread within a population. It has been suggested that selfish elements could be exploited to modify the genome of entire populations for medical and ecological applications. Here we report that trans...
Chapter
This book, which is divided into four parts, describes the advances in insect transgenesis. Part 1 deals with germline transformation technology while part 2 focuses on the application of transgenic insects, including plant insect pests and insect vectors (such as mosquitoes). Part 3 shows alternative transgenic approaches to modifying insect pheno...
Data
Table S2. Levels of codon bias for X-linked and autosomal sex-biased genes in A. gambiae. N indicates number of genes; Length indicates the mean number of base pair nucleotides for each category; ENC indicates the mean effective number of codons for each category; Fop indicates the mean frequency of optimal codons for each category. P-value for Man...