Increased drug and pesticide resistance has rendered many control programs for mosquito-borne diseases useless, resulting in an urgent need for new control strategies. Since malaria parasites must develop for up to two weeks in the mosquito there is opportunity to disrupt this development by enhancing mosquito innate immunity or shortening the mosquito's lifespan. The insulin/IGF-1 signaling cascade (ISC) has been shown to regulate both innate immunity and lifespan in invertebrates, and could be manipulated to reduce vector competence of mosquitoes. Based on our preliminary data, exogenous insulin and IGF-1 in the bloodmeal may also play major roles in the midgut and other tissues. To test these hypotheses, we will first determine whether exogenous human insulin and IGF-1 can stimulate the ISC in the midgut and other tissues, such as the fat body, in the mosquito Anopheles stephensi. We will also test the impact of these factors on oxidative stress and NO production, key components of aging, innate immunity, and signaling. Next we will engineer An. stephensi mosquitoes to express active forms of two ISC proteins, Akt and PTEN, in the midgut after a bloodmeal. Because AKT activates the midgut ISC and PTEN has the opposite effect, we will be able to answer three questions. 1) Does the midgut ISC regulate oxidative stress and in turn aging? 2) Does the midgut ISC affect signaling in other tissues? 3) Do changes to the ISC affect Plasmodium falciparum development? Finally, we will examine the impact of physiological levels of exogenous human insulin and IGF- 1 on the transgenic mosquitoes described above. Insulin levels in human blood can vary by as much as 10-fold after a meal and during malaria parasite infection. By understanding and taking into account the effects of this naturally occurring variation in human bloodmeals we can better predict the efficacy of Akt and PTEN overexpression on critical variables (e.g., lifespan and immunity) of vector competence. In summary, our proposed work will test both basic and applied hypotheses regarding the ISC and its impacts on mosquito physiology and vector competence that were conceptualized for Caenorhabditis elegans, Drosophila melanogaster and mammals. In addition, our work offers a different approach to the transgenic modification of mosquitoes to limit their vectorial capacity. Relevance: Many mosquito-borne disease agents, including malaria parasites, dengue virus, and West Nile virus, must develop in mosquitoes for extended periods before being transmitted to humans. We hope to enhance innate immunity and/or reduce average lifespan of a model mosquito below this development period so that transmission of malaria parasites is reduced or eliminated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073745-05
Application #
8278642
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Costero, Adriana
Project Start
2008-06-09
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$500,540
Indirect Cost
$98,678
Name
University of Arizona
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Pietri, Jose E; Pietri, Eduardo J; Potts, Rashaun et al. (2015) Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi. Dev Comp Immunol 53:134-44
Neafsey, Daniel E; Waterhouse, Robert M; Abai, Mohammad R et al. (2015) Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes. Science 347:1258522
Arik, Anam J; Hun, Lewis V; Quicke, Kendra et al. (2015) Increased Akt signaling in the mosquito fat body increases adult survivorship. FASEB J 29:1404-13
Cator, Lauren J; Pietri, Jose E; Murdock, Courtney C et al. (2015) Immune response and insulin signalling alter mosquito feeding behaviour to enhance malaria transmission potential. Sci Rep 5:11947
Wang, Bo; Pakpour, Nazzy; Napoli, Eleonora et al. (2015) Anopheles stephensi p38 MAPK signaling regulates innate immunity and bioenergetics during Plasmodium falciparum infection. Parasit Vectors 8:424
Luckhart, Shirley; Pakpour, Nazzy; Giulivi, Cecilia (2015) Host-pathogen interactions in malaria: cross-kingdom signaling and mitochondrial regulation. Curr Opin Immunol 36:73-9
Drexler, Anna L; Pietri, Jose E; Pakpour, Nazzy et al. (2014) Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi. PLoS Pathog 10:e1004231
Jiang, Xiaofang; Peery, Ashley; Hall, A Brantley et al. (2014) Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi. Genome Biol 15:459
Pietri, J E; Cheung, K W; Luckhart, S (2014) Knockdown of mitogen-activated protein kinase (MAPK) signalling in the midgut of Anopheles stephensi mosquitoes using antisense morpholinos. Insect Mol Biol 23:558-65
Pakpour, Nazzy; Camp, Lauren; Smithers, Hannah M et al. (2013) Protein kinase C-dependent signaling controls the midgut epithelial barrier to malaria parasite infection in anopheline mosquitoes. PLoS One 8:e76535

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