Expression of antiparasite peptides in Sand flies and Triatomine bugs inducing refractoriness to Leishmania and Trypanosoma cruzi mediated by CRISPR-Cas9 gene drives.


L Brandner-Garrod1; R Atherton1; F Olmo1; R Edwards1; L Thompson1; M E Rogers1; T Walker1; M Yeo1
1 London School of Hygiene & Tropical Medicine, UK


Leishamniasis and Chagas disease cause an enormous burden of human suffering. Vector control is difficult, there are no vaccines and drug regimes are not always efficacious. New approaches to control are needed. The recent development of CRISPR-Cas9 systems allows for precise genomic knockout and also insertions of exogenous DNA. In the context of vector-borne diseases two main approaches have been previously applied to Anopheline mosquitoes, namely to reduce reproductive capacity and secondarily to express antimalarial peptides mediated through highly efficient gene drives. Both approaches have achieved remarkable results in laboratory settings.

Here we aim to develop a platform to assess, introduce, and express anti-parasitic peptides applied to multiple sand fly and triatomine bug species mediated by CRISPR-Cas9 gene drives. Introduced traits spread rapidly through populations leading to a new approach to interrupt transmission for both Leishmaniasis and Chagas disease

Delivery of CRISPR-Cas9 components to insect embryos is difficult. Historically, microinjection has been the main approach for transfecting the embryos of disease vectors, although this has led to a number of potential research bottlenecks. The size and robust structure of triatomine eggs makes high throughput microinjection extremely unlikely. We have developed a non-microinjection delivery method to chemically mediate transgenesis in triatomine embryos, with successful delivery of plasmid constructs to embryos within 10 minutes of administering. In the context of sand flies, we are also able to introduce constructs via traditional microinjection approaches.

In tandem, we have developed a suite of CRISPR-Cas9 knockout constructs targeting non-lethal endogenous genes that are likely to induce a phenotypic effect or impact refractoriness to associated parasites. Transgenic constructs designed for the insertion of exogenous DNA and expression of candidate anti-parasitic peptides, validated through toxicity assays, and preferentially expressed in the midgut are being assessed. Selected peptide targets will be incorporated into constructs towards the development of full gene drive systems.

This approach has the potential to deliver a powerful and novel platform to interrupt disease transmission applied to both Leishmania and Trypanosoma cruzi.

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