Transmitted by mosquitoes, dengue is among the most important reemerging infectious diseases with an estimated 50 million to 100 million annual cases, 500,000 hospitalizations, and 22,000 deaths. Breaking the link between the mosquito vector and the dengue virus is the best option for protecting people. The endosymbiotic bacterium, Wolbachia, has long been promoted as potential vehicles for introducing disease- resistant genes into mosquitoes, making them refractory to the pathogens they carry. Pathogens are known to interact with Wolbachia and other symbiotic bacteria in several insect species. Given the large overlap in tissue distribution and intracellular localization of Wolbachia and dengue virus in mosquitoes, it is imperative that we characterize their interaction and determine the influence of Wolbachia on dengue transmission. Our long-term goal is to develop Wolbachia-based control strategies to block dengue virus transmission in mosquitoes. The objective of this proposal is to identify factors that enable Wolbachia-based population replacement to succeed in a way that reduces vector capacity to dengue virus. Our central hypotheses are that interactions between Wolbachia and dengue virus affect both the vector capacity of Ae. aegypti to dengue virus and the ability of Wolbachia to serve as a transgene driver. We formulated these hypotheses based on preliminary data that showed: 1) Wolbachia and dengue virus induce a host innate immune response and 2) the host immune response was correlated with the elimination of Wolbachia and suppression of dengue virus. The project has the five specific aims: 1). Initiate Wolbachia stock in Ae. aegypti. These stocks will be used on studies of strain- specific Wolbachia interactions with Ae. aegypti and dengue virus. 2). Identify molecular factors that determine the interactions between Wolbachia and dengue virus. We will design a novel dual-genome microarray, and utilize it to monitor gene expression changes in both Ae. aegypti and Wolbachia simultaneously in response to dengue infection. 3). Identify changes in dengue viral dynamics within Ae. aegypti due to Wolbachia infection. We will investigate the impact of Wolbachia on the oral susceptibility of mosquitoes to dengue virus, virus dissemination and transmission, and the potential of Wolbachia to select for more invasive dengue strains. 4). Identify Wolbachia-host interactions that are impaired by dengue infection. We will assess the impact of dengue virus on Wolbachia infection level, cytoplasmic incompatibility and maternal transmissibility. 5). Evaluate the mosquito fitness costs associated with dual infections of dengue virus and Wolbachia. We will focus on the fitness cost on the mosquito longevity, fecundity, and blood-feeding behavior. We anticipate this knowledge will improve genetic technology and its application in reducing vector capacity and blocking the transmission of dengue fever, thus, lead to better understand, treat, and prevent dengue fever.

Public Health Relevance

The research proposed here will aid in the development of the improved genetic methods to block the transmission of dengue fever, and improve our understanding on the ecology of dengue fever transmission in nature.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vector Biology Study Section (VB)
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Costero, Adriana
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Pan, Xiaoling; Pike, Andrew; Joshi, Deepak et al. (2018) The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti. ISME J 12:277-288
Zhang, Dongjing; Zhang, Meichun; Wu, Yu et al. (2017) Establishment of a medium-scale mosquito facility: optimization of the larval mass-rearing unit for Aedes albopictus (Diptera: Culicidae). Parasit Vectors 10:569
Joshi, Deepak; Pan, Xiaoling; McFadden, Michael J et al. (2017) The Maternally InheritableWolbachia wAlbB Induces Refractoriness toPlasmodium bergheiinAnopheles stephensi. Front Microbiol 8:366
Zhang, Dongjing; Lees, Rosemary Susan; Xi, Zhiyong et al. (2016) Combining the Sterile Insect Technique with the Incompatible Insect Technique: III-Robust Mating Competitiveness of Irradiated Triple Wolbachia-Infected Aedes albopictus Males under Semi-Field Conditions. PLoS One 11:e0151864
Zhang, Dongjing; Lees, Rosemary Susan; Xi, Zhiyong et al. (2015) Combining the Sterile Insect Technique with Wolbachia-Based Approaches: II--A Safer Approach to Aedes albopictus Population Suppression Programmes, Designed to Minimize the Consequences of Inadvertent Female Release. PLoS One 10:e0135194
Joshi, Deepak; McFadden, Michael J; Bevins, David et al. (2014) Wolbachia strain wAlbB confers both fitness costs and benefit on Anopheles stephensi. Parasit Vectors 7:336
Bian, Guowu; Joshi, Deepak; Dong, Yuemei et al. (2013) Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection. Science 340:748-51
Bian, Guowu; Zhou, Guoli; Lu, Peng et al. (2013) Replacing a native Wolbachia with a novel strain results in an increase in endosymbiont load and resistance to dengue virus in a mosquito vector. PLoS Negl Trop Dis 7:e2250
Pan, Xiaoling; Zhou, Guoli; Wu, Jiahong et al. (2012) Wolbachia induces reactive oxygen species (ROS)-dependent activation of the Toll pathway to control dengue virus in the mosquito Aedes aegypti. Proc Natl Acad Sci U S A 109:E23-31
Lu, Peng; Bian, Guowu; Pan, Xiaoling et al. (2012) Wolbachia induces density-dependent inhibition to dengue virus in mosquito cells. PLoS Negl Trop Dis 6:e1754

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