: Inducible nitric oxide synthase (NOS II) is a vital weapon in the anti-pathogen arsenal of both mammalian and invertebrate cells. In mammals, transforming growth factor-?1 (TGF-?1) modulates the host response to pathogens such as Plasmodium, the causative agent of malaria, via a prominent role in the regulation of NOS lI. High levels of NO appear to activate latent TGF?1 by S-nitrosation and subsequent inactivation of the endogenous neutralizer of TGF-?1 (the latency-associated peptide, LAP), while free heme, a potent pro-oxidant released in certain disease states, provides an additional mechanism for activation of latent TGF-?1. Among invertebrates, Anopheles mosquitoes limit malaria parasite development with an inducible synthesis of NO that is localized principally to the midgut. Anopheles stephensi NOS (AsNOS) shows remarkable conservation with vertebrate NOS genes; however, little is known about how AsNOS is regulated. Our Preliminary Studies reveal that human TGF?1, ingested by A. stephensi and activated in the midgut, regulates AsNOS and Plasmodium development. We have also identified a mosquito TGF-? homolog, As60A, whose expression is induced in the midgut and correlated with parasite infection, indicating that like its vertebrate counterpart TGF-?1, As60A is a marker of the host response to parasite infection. The act of blood feeding by Anopheles, therefore, creates a functional interface among vertebrate and invertebrate immune factors including AsNOS, NO, TGF-?1, and As60A in the midgut environment. We hypothesize that, in the mosquito midgut, (1) mammalian TGF-?1 is activated by heme released during blood digestion and induced mosquito NO and (2) that TGF-?1 and As60A activate intersecting signaling pathways to regulate target gene expression and parasite development. At a basic level, the studies proposed herein will establish whether cytokine control is a conserved feature of immune gene regulation among organisms that are separated by more than 500 million years of evolution. At a more applied level, the proposed research will likely have implications for the control of malaria. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050663-04
Application #
7006627
Study Section
Special Emphasis Panel (ZRG1-TMP (99))
Program Officer
Costero, Adriana
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$315,740
Indirect Cost
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
Murdock, Courtney C; Luckhart, Shirley; Cator, Lauren J (2017) Immunity, host physiology, and behaviour in infected vectors. Curr Opin Insect Sci 20:28-33
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
Surachetpong, Win; Singh, Naresh; Cheung, Kong Wai et al. (2009) MAPK ERK signaling regulates the TGF-beta1-dependent mosquito response to Plasmodium falciparum. PLoS Pathog 5:e1000366
Metukuri, Mallikarjuna Reddy; Namas, Rajaie; Gladstone, Chase et al. (2009) Activation of latent transforming growth factor-beta1 by nitric oxide in macrophages: role of soluble guanylate cyclase and MAP kinases. Wound Repair Regen 17:578-88
Drexler, Anna L; Vodovotz, Yoram; Luckhart, Shirley (2008) Plasmodium development in the mosquito: biology bottlenecks and opportunities for mathematical modeling. Trends Parasitol 24:333-6
Luckhart, Shirley; Lieber, Matthew J; Singh, Naresh et al. (2008) Low levels of mammalian TGF-beta1 are protective against malaria parasite infection, a paradox clarified in the mosquito host. Exp Parasitol 118:290-6
Kang, Mi-Ae; Mott, Tiffany M; Tapley, Erin C et al. (2008) Insulin regulates aging and oxidative stress in Anopheles stephensi. J Exp Biol 211:741-8
Luckhart, Shirley; Riehle, Michael A (2007) The insulin signaling cascade from nematodes to mammals: insights into innate immunity of Anopheles mosquitoes to malaria parasite infection. Dev Comp Immunol 31:647-56
Peterson, Tina M L; Gow, Andrew J; Luckhart, Shirley (2007) Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection. Free Radic Biol Med 42:132-42
Peterson, Tina M L; Luckhart, Shirley (2006) A mosquito 2-Cys peroxiredoxin protects against nitrosative and oxidative stresses associated with malaria parasite infection. Free Radic Biol Med 40:1067-82

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