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      Wolbachia Induces Density-Dependent Inhibition to Dengue Virus in Mosquito Cells

      1 , 2 , 2 , 1 , 2 , *

      PLoS Neglected Tropical Diseases

      Public Library of Science

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          Wolbachia is a maternal transmitted endosymbiotic bacterium that is estimated to infect up to 65% of insect species. The ability of Wolbachia to both induce viral interference and spread into mosquito vector population makes it possible to develop Wolbachia as a biological control agent for dengue control. While Wolbachia induces resistance to dengue virus in the transinfected Aedes aegypti mosquitoes, a similar effect was not observed in Aedes albopictus, which naturally carries Wolbachia infection but still serves as a dengue vector. In order to understand the mechanism of this lack of Wolbachia-mediated viral interference, we used both Ae. albopictus cell line (Aa23) and mosquitoes to characterize the impact of Wolbachia on dengue infection. A serial of sub-lethal doses of antibiotic treatment was used to partially remove Wolbachia in Aa23 cells and generate cell cultures with Wolbachia at different densities. We show that there is a strong negative linear correlation between the genome copy of Wolbachia and dengue virus with a dengue infection completely removed when Wolbacha density reaches a certain level. We then compared Wolbachia density between transinfected Ae. aegypti and naturally infected Ae. albopictus. The results show that Wolbachia density in midgut, fatbody and salivary gland of Ae. albopictus is 80-, 18-, and 24-fold less than that of Ae. aegypti, respectively. We provide evidence that Wolbachia density in somatic tissues of Ae. albopictus is too low to induce resistance to dengue virus. Our results will aid in understanding the mechanism of Wolbachia-mediated pathogen interference and developing novel methods to block disease transmission by mosquitoes carrying native Wolbachia infections.

          Author Summary

          Transmitted by mosquitoes, dengue virus causes the most important arbovirus disease in humans. Increasing problems in insecticide resistance and the lack of drugs and vaccines make it urgent to develop novel strategies for dengue control. Wolbachia is a maternally transmitted Gram-negative endosymbiotic bacterium that infects approximately 28% of mosquito species. It can not only spread within mosquito populations through its unique ability to manipulate mosquito reproduction but can also induce resistance to dengue virus in mosquito vectors. This leads to a genetic control strategy in which mosquito hosts are made to be inhospitable to dengue virus through population replacement. However, it is challenged by the fact that Ae. albopictus naturally carries Wolbachia infections but still services as a dengue vector. In this study we show the native Wolbachia induces a resistance to dengue virus in Wolbachia density-dependent manner in Ae. albopictus. With a decrease in Wolbachia density within the host cells, dengue infection increases dramatically. We provide evidence that a very low Wolbachia density in mosquito tissues where dengue virus will reside and travel could contribute to absence of Wolbachia-mediated resistance to dengue virus in Ae. albopictus.

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          Wolbachia: master manipulators of invertebrate biology.

          Wolbachia are common intracellular bacteria that are found in arthropods and nematodes. These alphaproteobacteria endosymbionts are transmitted vertically through host eggs and alter host biology in diverse ways, including the induction of reproductive manipulations, such as feminization, parthenogenesis, male killing and sperm-egg incompatibility. They can also move horizontally across species boundaries, resulting in a widespread and global distribution in diverse invertebrate hosts. Here, we review the basic biology of Wolbachia, with emphasis on recent advances in our understanding of these fascinating endosymbionts.
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            A Wolbachia symbiont in Aedes aegypti limits infection with dengue, Chikungunya, and Plasmodium.

            Wolbachia are maternally inherited intracellular bacterial symbionts that are estimated to infect more than 60% of all insect species. While Wolbachia is commonly found in many mosquitoes it is absent from the species that are considered to be of major importance for the transmission of human pathogens. The successful introduction of a life-shortening strain of Wolbachia into the dengue vector Aedes aegypti that halves adult lifespan has recently been reported. Here we show that this same Wolbachia infection also directly inhibits the ability of a range of pathogens to infect this mosquito species. The effect is Wolbachia strain specific and relates to Wolbachia priming of the mosquito innate immune system and potentially competition for limiting cellular resources required for pathogen replication. We suggest that this Wolbachia-mediated pathogen interference may work synergistically with the life-shortening strategy proposed previously to provide a powerful approach for the control of insect transmitted diseases. Copyright 2009 Elsevier Inc. All rights reserved.
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              Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission.

              Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.

                Author and article information

                Role: Editor
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                July 2012
                24 July 2012
                : 6
                : 7
                [1 ]Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, United States of America
                [2 ]Department of Entomology, Michigan State University, East Lansing, Michigan, United States of America
                Monash University, Australia
                Author notes

                Conceived and designed the experiments: PL ZX. Performed the experiments: PL GB XP. Analyzed the data: PL ZX. Contributed reagents/materials/analysis tools: PL ZX. Wrote the paper: PL ZX.

                Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 8
                Research Article
                Vector Biology
                Viral Vectors
                Emerging Viral Diseases
                Emerging Infectious Diseases
                Host-Pathogen Interaction
                Microbial Control

                Infectious disease & Microbiology


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