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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080799-05
Application #
8487341
Study Section
Special Emphasis Panel (ZRG1-IDM-R (02))
Program Officer
Costero, Adriana
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$601,828
Indirect Cost
$103,906
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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
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
Brenton, Ashley A; Souvannaseng, Lattha; Cheung, Kong et al. (2014) Engineered single nucleotide polymorphisms in the mosquito MEK docking site alter Plasmodium berghei development in Anopheles gambiae. Parasit Vectors 7:287
Aerts, Jean-Marie; Haddad, Wassim M; An, Gary et al. (2014) From data patterns to mechanistic models in acute critical illness. J Crit Care 29:604-10
Luckhart, Shirley; Giulivi, Cecilia; Drexler, Anna L et al. (2013) Sustained activation of Akt elicits mitochondrial dysfunction to block Plasmodium falciparum infection in the mosquito host. PLoS Pathog 9:e1003180
Pakpour, Nazzy; Akman-Anderson, Leyla; Vodovotz, Yoram et al. (2013) The effects of ingested mammalian blood factors on vector arthropod immunity and physiology. Microbes Infect 15:243-54
Price, Ian; Ermentrout, Bard; Zamora, Ruben et al. (2013) In vivo, in vitro, and in silico studies suggest a conserved immune module that regulates malaria parasite transmission from mammals to mosquitoes. J Theor Biol 334:173-86
Vodovotz, Yoram; Billiar, Timothy R (2013) In silico modeling: methods and applications to trauma and sepsis. Crit Care Med 41:2008-14
Pakpour, Nazzy; Corby-Harris, Vanessa; Green, Gabriel P et al. (2012) Ingested human insulin inhibits the mosquito NF-?B-dependent immune response to Plasmodium falciparum. Infect Immun 80:2141-9

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