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Kosakonia & Chromobacterium Vs KOSAKONIA & CHROMOBACTERIUM VS. MALARIA & DENGUE – INSIGHTS INTO ANTIPATHOGENIC STRATEGIES OF MOSQUITO MIDGUT BACTERIA by Raúl G. Saraiva A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy. Baltimore, Maryland March, 2018 © Raúl G. Saraiva 2018 All rights reserved ABSTRACT Malaria and dengue are arguably today’s most relevant tropical diseases vectored by Anopheles and Aedes spp. mosquitoes, respectively. Both pathogens enter the vector through a blood meal from an infected individual and inhabit the mosquito’s midgut even if briefly, encountering a plethora of antipathogenic factors. To those, there is an unequivocal contribution of the mosquito gut microbiota, as discussed herein. In this work, we explore the role of individual members of the mosquito gut microbiota in limiting the vector’s ability to acquire and transmit Plasmodium spp. and the dengue virus. A Kosakonia isolate from an anopheline in Zambia is shown to interfere with Plasmodium development by inducing the shutdown of the parasite’s antioxidant response. A Chromobacterium species isolated from Aedes aegypti in Panama secretes an aminopeptidase that can ablate infectivity by the dengue virus, while also secreting the histone deacetylase romidepsin that can prevent P. falciparum maturation in Anopheles gambiae. These findings constitute the first mechanistic descriptions on how certain members of the mosquito microbiota may exercise a pivotal role in the control of disease transmission, generating key knowledge towards the understanding of the dynamics of both malaria and dengue. At the same time, strategies can be devised to employ our conclusions towards the development of novel antimalarial and anti-DENV regimens, or towards the deployment of microbiota-shifting approaches by which the enrichment in pathogen-protective bacteria within field mosquito populations is promoted. ii ACKNOWLEDGEMENTS I would like to express my sincere gratitude for everyone who guide me, helped me and supported me throughout this project: Dr. George Dimopoulos for taking me as an advisee and understanding something fruitful would come out of our complementary expertises. Drs. Jürgen Bosch, Marcelo Jacobs-Lorena, Cynthia Sears, Photini Sinnis and Craig Townsend for all their contributions as members of my advising committee; the collaboration of Drs. Bosch and Townsend was instrumental for the success of this study. Present and past members of the Dimopoulos group for the guidance and camaraderie, especially those that are co-authors in resulting publications for their hardwork and dedication. The MMI department for its people and for the financial support to my journey, together with Boehringer Ingelheim Fonds, Fulbright and Emergent Biosolutions. The Fulbright Association, PAPS and JHSPH Student Assembly for accepting me as a volunteer and superbly complementing my student experience. My friends here, back home and across the world for making this a richer adventure than I could ever expect. My parents and family for all the love. iii TABLE OF CONTENTS CHAPTER 1. Introduction ....................................................................................................... 1 1.1. Malaria parasites encounter a bottleneck in the Anopheles midgut ..................................... 2 1.1.1. The peritrophic matrix and epithelial barriers ............................................................... 4 1.1.2. Immunosurveillance ...................................................................................................... 7 1.1.3. A complement-like defense system ............................................................................... 8 1.1.4. The melanization defense system ................................................................................ 10 1.1.5. Oxidative and nitrosative stresses in anti-Plasmodium defense .................................. 11 1.1.6. Other defense effectors ................................................................................................ 13 1.1.7. The influence of midgut microbiota on Plasmodium infection ................................... 15 1.2. Dengue infection is limited by factors in the mosquito gut ............................................... 17 1.2.1. Antiviral defense pathways ......................................................................................... 18 1.2.2. Apoptosis of host cells as a potential antiviral mechanism ......................................... 21 1.2.3. Role of midgut bacteria in the anti-DENV response ................................................... 21 1.3. Bacterial natural products in the fight against mosquito-borne disease ............................. 22 1.3.1. Antimalarials of bacterial origin .................................................................................. 22 1.3.2. Bacteria-produced metabolites as dengue antivirals ................................................... 26 1.3.3. A role for metabolites produced by the mosquito gut microbiota? ............................. 27 1.4. Aims of this work ............................................................................................................... 29 iv Authors’ contributions............................................................................................................... 30 CHAPTER 2. Functional genomic analyzes of Kosakonia, Anopheles and Plasmodium reciprocal interactions that impact vector competence ................................................................. 31 2.1. Summary ............................................................................................................................ 32 2.2. Background ........................................................................................................................ 34 2.3. Methodology ...................................................................................................................... 36 2.3.1. Mosquito rearing and antibiotic treatment ................................................................... 36 2.3.2. Bacteria cocktail preparation ....................................................................................... 36 2.3.3. Introduction of bacteria through sugar or blood meals ................................................ 37 2.3.4. Anopheles gambiae midgut selection of Kco_Z .......................................................... 37 2.3.5. Colonization experiments and DNA extraction........................................................... 37 2.3.6. Absolute qPCR quantification ..................................................................................... 38 2.3.7. Relative qPCR quantification ...................................................................................... 39 2.3.8. Longevity, fecundity, and fertility assays .................................................................... 40 2.3.9. Plasmodium infection assays ....................................................................................... 41 2.3.10. Kco_Z genome sequencing and transcriptome analysis ............................................ 41 2.3.11. In vitro parasite culture and co-culture with bacteria ................................................ 42 2.4. Results ................................................................................................................................ 44 2.4.1. Colonization of the Anopheles gambiae midgut by Kco_Z ......................................... 44 v 2.4.2. Inhibition of Plasmodium sporogonic development following sugar-meal introduction of Kco_Z ................................................................................................................................ 45 2.4.3. Kco_Z influence on mosquito fitness parameters ........................................................ 46 2.4.4. Kco_Z genome analysis ............................................................................................... 48 2.4.5. Transcriptomic survey of Kco_Z genes that mediate selection in the mosquito midgut environment ........................................................................................................................... 48 2.4.6. Transcriptomic survey for Kco_Z-encoded Plasmodium inhibition factors ................ 51 2.4.7. Influence of Kco_Z on Plasmodium antioxidant gene expression .............................. 53 2.5. Discussion .......................................................................................................................... 56 Authors’ contributions............................................................................................................... 58 CHAPTER 3. Chromobacterium spp. mediate their antimalarial activity through secretion of the HDAC inhibitor romidepsin.................................................................................................... 59 3.1. Summary ............................................................................................................................ 60 3.2. Background ........................................................................................................................ 61 3.3. Methodology ...................................................................................................................... 63 3.3.1. Bacterial cultures and n-butanol extraction ................................................................. 63 3.3.2. Plasmodium falciparum strains and cultivation .........................................................
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