Our work to date has focused on understanding how ingested mammalian transforming growth factor (TGF)-?1 is activated, regulates mosquito Smad signaling and endogenous TGF-?s, and ultimately reduces malaria parasite loads in A. stephensi. This work led to the study of signaling pathways by which this inter-species crosstalk occurs, guided by advances in the field of mammalian immunity and inflammation. In mammals, four interacting regulatory pathways are associated with immunity: the nuclear factor (NF)-?B pathway and the three mitogen-activated protein kinase (MAPK) pathways, including JNK, ERK and p38-dependent pathways. We have shown that TGF-?1 signaling in A. stephensi cells is regulated by redox chemistry and involves differential activation of the A. stephensi homologs of ERK, JNK, and p38. We have also identified other bloodmeal-derived factors including insulin, two parasite toxins, and two mammalian inflammatory mediators that, like TGF-?1, may function as signals to A. stephensi cells. Indeed, our preliminary data suggest that these factors also regulate the activation of A. stephensi ERK, JNK, and p38. Our long-term goal is to manipulate a highly complex ecological system--which consists of the mosquito host, the mammalian host, and the parasite--as a whole in order to block malaria infection. We hypothesize that a coordinated network of pathways (MAPKs, Smads, NF-?B) regulates the mosquito response to infection. Moreover, the inflammatory outcomes driven by these signaling pathways set in motion new signals that must be interpreted by all three members of this ecosystem. This challenge is daunting, given the complexity of the inflammatory response in a single species. Yet, we have shown that this complexity can be addressed rationally through inter-connected experimental approaches and computational simulations. As such, we will leverage our experience with this system and with computational simulations of inflammation at multiple scales, from the intracellular level to the multi-organismal level, including preliminary models of inter-species crosstalk in the setting of malaria. We propose that this integrated approach will allow us to discern not only the mechanisms operant in the process of immune crosstalk, but also explain unexpected behavior in the system and define the """"""""master switches"""""""" - the crosstalking extracellular factors and signaling pathway components - that have the greatest potential impact on parasite development in A. stephensi.

Public Health Relevance

The mosquito Anopheles stephensi is an important vector of the human malaria parasite Plasmodium falciparum. Many studies have focused on individual gene products that respond to and destroy these parasites, but there is little to no information on the coordinated regulation of these responses. Our studies will elucidate this coordination and develop mathematical and statistical models of the biological interface of the mosquito, the parasite, and the mammalian host. These studies will serve to identify the master switches that control parasite development in the mosquito. In the long-term, we propose that this information will contribute to novel malaria control methods.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-R (02))
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Costero, Adriana
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University of California Davis
Schools of Medicine
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Pietri, Jose E; Pakpour, Nazzy; Napoli, Eleonora et al. (2016) Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism. Biochem J 473:3487-3503
Luckhart, Shirley; Pakpour, Nazzy; Giulivi, Cecilia (2015) Host-pathogen interactions in malaria: cross-kingdom signaling and mitochondrial regulation. Curr Opin Immunol 36:73-9
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
Namas, Rami A; Mi, Qi; Namas, Rajaie et al. (2015) Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation. Antioxid Redox Signal 23:1370-87
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
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
Pakpour, Nazzy; Riehle, Michael A; Luckhart, Shirley (2014) Effects of ingested vertebrate-derived factors on insect immune responses. Curr Opin Insect Sci 3:1-5
Azhar, Nabil; Vodovotz, Yoram (2014) Innate immunity in disease: insights from mathematical modeling and analysis. Adv Exp Med Biol 844:227-43
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
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

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