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Infect. Immun. doi:10.1128/IAI.00645-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Induction of Nitric Oxide Synthase and Activation of Signaling Proteins in Anopheles Mosquitoes by Malaria Pigment Hemozoin

Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA, Department of Microbiology and Immunology, McGill University, Lyman Duff Medical Building, 3775 University Street, Montreal, QC H3A 2B4, Canada

^* To whom correspondence should be addressed. Email: sluckhart{at}ucdavis.edu.

	Abstract

Anopheles stephensi, a major vector for malaria parasite transmission, responds to Plasmodium infection by synthesis of inflammatory levels of nitric oxide (NO), which can limit parasite development in the midgut. We have previously shown that Plasmodium falciparum glycosylphosphatidylinositols (PfGPIs) can induce A. stephensi NO synthase (AsNOS) expression in the midgut epithelium in vivo in a manner similar to the induction of cytokines and NO by PfGPIs in mammalian cells. In mosquito cells, signaling by PfGPIs and P. falciparum merozoites is mediated through Akt/protein kinase B (PKB), the mitogen-activated protein kinase kinase (MAPKK) DSOR1, and extracellular signal-regulated kinase (ERK). In mammalian cells, a second parasite factor, malaria pigment or hemozoin (Hz) signals NOS induction through ERK- and nuclear factor kappa B (NF-B)-dependent pathways and has been demonstrated to be a novel proinflammatory ligand for Toll-like receptor 9 (TLR9). In this study, we demonstrate that Hz can also induce AsNOS gene expression in immortalized Anopheles stephensi and Anopheles gambiae cell lines in vitro and in A. stephensi midgut tissue in vivo. In mosquito cells, Hz signaling is mediated through transforming growth factor-beta (TGF-)-associated kinase 1 (TAK1), Akt/PKB, ERK and atypical protein kinase C zeta/lambda (aPKC/). Our results show that Hz is a prominent parasite-derived signal for Anopheles and that signaling pathways activated by PfGPIs and Hz have both unique and shared components. Taken together with our previous findings, our data indicate that parasite signaling of innate immunity is conserved in mosquito and mammalian cells.