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

• Published in: Infection and Immunity Vol. 75; no. 8; pp. 4012 - 4019
• Main Authors: Akman-Anderson, Leyla, Olivier, Martin, Luckhart, Shirley
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.08.2007
• Subjects: Animals; Anopheles - enzymology; Anopheles - metabolism; Anopheles - parasitology; Anopheles gambiae; Anopheles stephensi; Biological and medical sciences; Cell Line; Enzyme Induction; Extracellular Signal-Regulated MAP Kinases - immunology; Fungal and Parasitic Infections; Gastrointestinal Tract - immunology; Hemeproteins - immunology; Human protozoal diseases; Immunity, Innate; Infectious diseases; Malaria; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; MAP Kinase Kinase Kinases - immunology; Medical sciences; Nitric Oxide Synthase - biosynthesis; Parasitic diseases; Plasmodium falciparum; Plasmodium falciparum - immunology; Protein Kinase C - immunology; Proto-Oncogene Proteins c-akt - immunology; Protozoal diseases; Signal Transduction - immunology; Up-Regulation; Protozoal disease; Malaria; Enzyme; Insecta; Parasitosis; Nitric-oxide synthase; Protein; Infection; Anopheles; Arthropoda; Culicidae; Pigments; Oxidoreductases; Invertebrata; Diptera
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00645-07

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 manner in which cytokines and NO are induced by PfGPIs in mammalian cells. In mosquito cells, signaling by PfGPIs and P. falciparum merozoites is mediated through Akt/protein kinase B (Akt/PKB), the mitogen-activated protein kinase kinase 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-dependent pathways and has been demonstrated to be a novel proinflammatory ligand for Toll-like receptor 9. In this study, we demonstrate that Hz can also induce AsNOS gene expression in immortalized A. 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 β-associated kinase 1, Akt/PKB, ERK, and atypical protein kinase C zeta/lambda. 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. Together with our previous findings, our data indicate that parasite signaling of innate immunity is conserved in mosquito and mammalian cells.