Species-specific Yeast RNAi Pesticides for Sand Fly Control

Sand flies are the vectors of several disease pathogens that infect humans, the most devastating being leishmaniasis. Leishmaniasis, a neglected tropical disease, is a serious public health concern, particularly in resource-poor settings, and is endemic in over 99 countries both in the Old and New World, affecting more than 12 million people globally. In Asia, Africa, and Europe, leishmaniasis is spread by sand flies of the genus Phlebotomus, and in the Americas, the genus Lutzomyia. Treatments for leishmaniasis are either highly toxic, require long intravenous treatment regiments, or are expensive, and drug resistance is emerging. With no vaccine currently available to protect humans, the disease vectors pose a significant threat to 310 million of people worldwide. The ecological niche and natural breeding sites of sand flies are diverse, ranging from sylvatic landscapes in forests to urban areas that include the peridomestic environments. The increasing close human–sand fly associations are giving rise to greater risks of Leishmania transmission in the home environment; therefore, there is an urgent need to control the vectors during the immature and adult stages to reduce risk of disease transmission. Although sand fly chemical-based control is a key component of leishmaniasis control, the effectiveness and success of this intervention is limited due to insecticide resistance and non-target effects. Our research program has successfully demonstrated yeast RNAi-based insecticides as innovative, environmentally safe and highly effective for direct control of vector mosquitoes. Although both mosquitoes and sand flies are important blood- sucking vectors of human pathogens occurring in the peridomestic environment, the innovative new yeast insecticides have not yet been assessed in leishmaniasis vectors. The objective of the proposed research is to evaluate the potential for RNAi yeast-based technologies to facilitate the control of sand flies. The proposed investigation will test the hypothesis, which is supported by strong preliminary data, that interfering RNA produced and delivered in Saccharomyces cerevisiae can be utilized as insecticidal agents targeting sand flies. The specific aims are to 1) identify RNAi yeast formulations that can be used to target sand flies, 2) evaluate RNAi-based yeast attractive targeted sugar baits (ATSBs) for the control of adult sand flies, and 3) develop and assess sand fly female-specific RNAi yeast larvicides that can facilitate male sex-sorting. The identification of female-specific larvicides will permit the design of an RNAi yeast-based mass rearing diet that can facilitate production of fit adult males that can be deployed for mass release of sterile males to suppress sand fly populations in targeted areas of disease endemic countries. The aims will be pursued through laboratory and simulated field trials that are designed to achieve the expected outcome of identifying a new class of RNAi yeast-based insecticides to facilitate sand fly control for the reduction of leishmaniasis transmission. Project Number: 1R21AI196489-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: MARY MCDOWELL | Institution: UNIVERSITY OF NOTRE DAME, NOTRE DAME, IN | Award Amount: $464,176 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 DCAI-X (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19648901