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Plasmodium-Induced Nitrosative Stress in Anopheles Stephensi: the Cost of Host Defense

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Plasmodium-Induced Nitrosative Stress in Anopheles Stephensi: the Cost of Host Defense Plasmodium-Induced Nitrosative Stress in Anopheles stephensi: The Cost of Host Defense Tina Marie Loane Peterson Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements of the degree of Doctor of Philosophy in Biochemistry Shirley Luckhart, Advisor Glenda Gillaspy Peter J. Kennelly Timothy J. Larson Zhijian (Jake) Tu May 23, 2005 Blacksburg, Virginia Key words: Anopheles, biochemistry, malaria, nitric oxide, nitrosative stress, peroxiredoxin, Plasmodium Copyright © May 23, 2005. Tina M. L. Peterson Plasmodium-Induced Nitrosative Stress in Anopheles stephensi: The Cost of Host Defense By Tina Marie Loane Peterson Shirley Luckhart, Advisor Department of Biochemistry ABSTRACT Both vertebrates and anopheline mosquitoes inhibit Plasmodium spp. (malaria parasite) development via induction of nitric oxide (•NO) synthase. Expression of Anopheles stephensi •NO synthase (AsNOS) is induced in the midgut epithelium beginning at 6 h following a Plasmodium berghei-infected blood meal. •NO reacts readily with other biocompounds forming a variety of reactive nitrogen intermediates (RNIs) that may impose a nitrosative stress. These RNIs are proposed to be responsible for the AsNOS-dependent inhibition of Plasmodium development. In my studies, I identified several RNIs that are induced in the blood-filled midgut • - - in response to Plasmodium infection. Stable end products of NO (NO3 and NO2 ), measured using a modified Griess assay, are elevated in infected midguts at 24 h post- blood meal (pBM). Further studies using chemical reduction-chemiluminescence with Hg displacement showed that infected midguts contained elevated levels of potentially toxic higher oxides of nitrogen (NOx), but S-nitrosothiol (SNO) and nitrite levels did not differ between infected and uninfected midguts at 12.5 and 24 h pBM. Thus, nitrates contributed to elevated NOx levels. SNO-biotin switch westerns indicated that S- nitrosated midgut proteins change over the course of blood meal digestion, but not in response to infection. Photolysis-chemiluminescence was used to release and detect bound •NO from compounds in blood-filled midguts dissected from 0-33 h pBM. Results showed increased •NO levels in Plasmodium-infected midgut lysates beginning at 8 h, with significant increases at 12.5-13.5 h and 24-25.5 h pBM and peak levels at 20-24 h. Photolyzed •NO is derived from SNOs and metal nitrosyls. Since SNO concentrations did not change in response to infection, I proposed that metal nitrosyls, specifically Fe nitrosyl hemoglobin (nitrosylHb) based on the concentration of hemoglobin, were elevated in the infected midgut. At 12-24 h pBM, levels of midgut RNIs in infected mosquitoes were typical of levels measured during mammalian septic inflammation. The inverse relationship between AsNOS activity and parasite abundance indicates that nitrosative stress has a detrimental effect on parasite development. However, nitrosative stress may impact mosquito tissues as well in a manner analogous to mammalian tissue damage during inflammation. Elevated levels of nitrotyrosine (NTYR), a marker for nitrosative stress in many mammalian disease states, were detected in tissues of parasite-infected A. stephensi at 24 h pBM. Greater nitration of tyrosine residues was detected in the blood bolus, midgut epithelium, eggs and fat body. In the midgut, Hb remained in an oxygenated state for the duration of blood digestion. The reaction between •NO and oxyhemoglobin (oxyHb) can result in the formation of nitrate and methemoglobin (metHb). Although nitrate levels were elevated in response to parasite infection, there was little to no metHb present in the mosquito midgut. The simultaneous presence of nitrates, nitrosylHb, oxyHb, and NTYR, together with a lack of elevated nitrites and metHb, suggested that alternative reaction mechanisms involving •NO had occurred in the reducing environment of the midgut. In addition, I proposed that nitroxyl and peroxynitrite participated in reactions that yielded observed midgut RNIs. To cope with the parasite-induced nitrosative stress, cellular defenses in the mosquito may be induced to minimize self damage. I proposed that peroxiredoxins (Prx), enzymes that can detoxify peroxides and peroxynitrite, may protect A. stephensi from nitrosative stress. Six Prx genes were identified in the A. gambiae genome based on homology with known D. melanogaster Prxs. I identified one A. stephensi Prx, AsPrx, that shared 78% amino acid identity with a D. melanogaster 2-Cys Prx known to protect fly cells against various oxidative stresses. AsPrx was expressed in the midgut epithelium and is encoded by a single-copy, intronless gene. Quantitative RT-PCR analyses confirmed that induction of AsPrx expression in the midgut was correlated with malaria parasite infection and nitrosative stress. To determine whether AsPrx could protect against RNI- and ROS-mediated cell death, transient transfection protocols were iii established for AsPrx overexpression in D. melanogaster (S2) and A. stephensi (MSQ43) cells and for AsPrx gene silencing using RNA interference in MSQ43 cells. Viability assays in MSQ43 cells showed that AsPrx conferred protection against hydrogen peroxide, •NO, nitroxyl and peroxynitrite. These data suggested that the •NO-mediated defense response is toxic to both host and parasite. However, AsPrx may shift the balance in favor of the mosquito. iv DEDICATION To Annika, without whom I would have written this dissertation a lot faster but probably had a mental break down in the process. Your pleasant distractions kept me sane! v ACKNOWLEGDEMENTS I wish to thank my advisor, Dr. Shirley Luckhart, for her guidance and support of my research. Her example of enthusiasm and perseverance helped to keep my goals in focus when I did not think I had it in me to continue. Her encouragement and frankness have made me a better scientist and made me understand what it takes to become a professional in academia. She was equal parts role model, friend and personal cheerleader. I also wish to thank my graduate committee members, Drs. Gillaspy, Kennelly, Larson and Tu, for serving on my committee. I appreciated their advice as well as the use of their lab equipment and supplies. I also wish to thank Drs. Tom Sitz and John Hess. I am deeply grateful to Dr. Andrew Gow for all of his help with the midgut RNI analyses. His assistance with the NO-related portion of my work was invaluable. I would also like to acknowledge his technicians, Trevor Fusaro and Christiana Davis, for their help when I visited their lab. Many thanks to my lab “mates”, Dr. Andrea Crampton, Dr. Junghwa Lim, Matthew Lieber, Dr. Theresa “Tree” Dellinger and Michelle Garlic McClanan, who made my days in the lab most… interesting. A special thanks to Andrea and Ken Hurley for getting my butt out of the lab to regain my sanity, and to Tree for her help getting the cell viability studies done before I “popped”. I am very appreciative of Randy Saunders for maintaining the insectary and performing the feeds. I would also like to thank the library staff for their great service sending me all of the research materials necessary for completing my writing. And lastly, thank you to my husband Todd Peterson. I never would have pursued this degree had it not been for him. Although he didn’t always understand what I was doing or why, he stuck by me. I know this was especially tough when it meant living in different states for almost two years and missing out on the day to day tribulations of our pregnancy. Nevertheless, he supported my decision to continue on. vi TABLE OF CONTENTS ABSTRACT....................................................................................................................... ii DEDICATION................................................................................................................... v ACKNOWLEGDEMENTS ............................................................................................ vi TABLE OF CONTENTS ............................................................................................... vii LIST OF FIGURES ......................................................................................................... xi LIST OF TABLES .........................................................................................................xiii LIST OF ABBREVIATIONS ....................................................................................... xiv CHAPTER ONE: Literature review............................................................................... 1 IDENTIFYING THE CAUSE OF MALARIA .......................................................... 1 EARLY CONTROL OF MALARIA .......................................................................... 2 RE-EMERGENCE OF MALARIA ............................................................................ 3 PLASMODIUM BERGHEI LIFE CYCLE IN ANOPHELES STEPHENSI ........... 4 GENERAL IMMUNE RESPONSE OF INSECTS ................................................... 6 NITRIC OXIDE SYNTHASE (NOS).......................................................................... 7 ANOPHELES STEPHENSI NOS (AsNOS)................................................................ 9 AsNOS AND PLASMODIUM INFECTION ............................................................ 11 ANOPHELES MIDGUT ENVIRONMENT............................................................. 14 •NO AND ITS CHEMISTRY....................................................................................
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