Strategies of the home-team: symbioses exploited for vector-borne disease control

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Abstract

Symbioses between eukaryotes and unicellular organisms are quite common, with examples copiously disseminated throughout the earth's biota. Arthropods, in particular, owe much of their ecological success to their microbial flora, which often provide supplements either lacking in the limited host diet or which the hosts are unable to synthesize. In addition to harboring beneficial microbes, many arthropods (vectors) also transmit pathogens to the animals and plants upon which they prey. Vector-borne diseases exact a high public health burden and additionally have a devastating impact on livestock and agriculture. Recent scientific discoveries have resulted in the development of powerful technologies for studying the vector's biology, to discover the weak links in disease transmission. One of the more challenging applications of these developments is transgenesis, which allows for insertion of foreign DNA into the insect's genome to modify its phenotype. In this review, we discuss an approach in which the naturally occurring commensal flora of insects are manipulated to express products that render their host environment inhospitable for pathogen transmission. Replacing susceptible insect genotypes with modified counterparts with reduced pathogen transmission ability, might provide a new set of armaments in the battle for vector-borne disease reduction.

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Interactions between symbionts and hosts

Eukaryotic hosts can acquire their symbionts by maternal inheritance (transovarial or acquisition in utero) or environmental acquisition (via the surrounding habitat, with a new infection established at each generation) (Table 1) [5]. While residing in the bodies of their multicellular hosts, most symbiotic microbes encounter an elaborate series of obstacles. Similar to pathogens, these beneficial bacteria first have to adhere to and enter their host cells (often specialized tissues and cell

Symbiosis in tsetse

Tsetse flies (Diptera: Glossinidae) harbor three distinct microorganisms that exhibit different forms of symbiotic relations [30]. Two of the organisms harbored in the gut tissue of all tsetse flies analyzed are members of the Enterobacteriaceae: the obligate mutualist genus Wigglesworthia glossinidia 31, 32 and the commensal genus Sodalis glossinidius 33, 34. The third symbiont present in some tsetse populations is related to the parasitic microbe Wolbachia pipientis, an α-Proteobacteria 35, 36

Obligate mutualist Wigglesworthia

Wigglesworthia cells lie free within the cytoplasm of bacteriocytes that make up the bacteriome structure located in anterior midgut (Figure 3). Recently, the genome of Wigglesworthia was completely sequenced and found to be 697 724 base pairs in size, encoding 621 predicted protein coding sequences (CDSs) [15]. Analysis of the CDSs indicate that Wigglesworthia has retained the ability to synthesize various vitamin metabolites, including biotin, thiazole, lipoic acid, flavin adenine

Commensal Sodalis

In addition to harboring Wigglesworthia, all tsetse flies analyzed from the field harbor the gut commensal Sodalis (for companion in Latin) [40]. Members of the facultative symbiont genus Sodalis from distant tsetse species do not exhibit significant phylogenetic differences based on their 16S rDNA sequence [25], suggesting a relatively younger symbiotic establishment. Sodalis has a wide tissue tropism, harbored both inter- and extracellularly, principally in the midgut tissue, but also in the

Development of transgenic technologies for vector-borne disease control

In addition to housing beneficial microbes, many insects (vectors) also transmit disease-causing organisms to the animals and plants upon which they feed. Control of these diseases, such as malaria, dengue, African trypanosomiasis, Chagas disease and leishmaniasis, has re-emerged as an important priority for the medical and scientific community. Development of efficacious vaccines has been difficult, and the emergence and rapid spread of resistance in parasites to the commonly used and

Genetic transformation systems

The process of genetic transformation in many insects has been achieved by the microinjection of various transposable elements (plasmid or viral vectors) into synctial embryos (germline transformation) [46]. The transposable elements insert themselves randomly into insect DNA, resulting in germline transformation, whereby the transgene is passed on to every individual cell of the genetically modified organism. Marker genes carried by the transposable element help to identify transgenic

Characterization of antipathogenic gene products

The discovery of gene products that can have an adverse effect on pathogen development (effector genes) when expressed in a vector background is a crucial step in transgenic technology. The identification of monoclonal antibodies (mABs) with parasite-transmission blocking characteristics, and their subsequent expression as single-chain antibody gene fragments, provides a vast array of potential antipathogenic effectors. Towards this goal, transmission-blocking antibodies affecting the major

Possible gene driving systems

An important applied aspect of all transgenic work is the ability to spread the laboratory-engineered phenotypes into natural populations. The Wolbachia symbiont, which has infected a wide-range of invertebrate hosts [66], including several tsetse fly species, provides one potential drive mechanism. The functional presence of Wolbachia has been shown to result in a variety of reproductive abnormalities in the various invertebrate hosts they infect. One of these abnormalities is termed

Potential roles of trypanosome-refractory tsetse flies in disease control

The eventual replacement of parasite-susceptible vector populations with the engineered refractory flies could provide an additional strategy to reduce disease. If Wolbachia infections in tsetse flies do express strong CI phenotypes, the two symbiotic systems can be coupled to mediate the spread of the refractory phenotypes conferred by the recSodalis into natural populations. It is important that the fidelity of the maternal linkage between the two symbiotic systems remains high, to ensure

Concluding remarks

The advancements in the field of symbiosis bring forth new avenues that can lead to a broad range of applications, ranging from the protection and treatment of their partners against harmful agents (invading pathogens) to the manipulation of undesirable host traits (i.e. pathogen transmission in the case of vector insects). For the many insect-borne diseases of animals and plants, for which adequate control is currently lacking, these strategies promise novel control tools. The commensals of

Acknowledgements

We are grateful to past and present members of our group, Xiao-ai Chen, Song Li, Quiying Cheng, Jian Yan, Leyla Akman, Zhengrong Hao, Patricia M. Strickler, Irene Kasumba, Dana Nayduch and Brian Weiss, and to colleagues John Brownstein, Masahira Hattori, Hidemi Watanabe, Alan Robinson, Michael Lehane, Terry Pearson, Wendy Gibson, Joseph Ndung'u, Dean Moolo and Saini Kumar for their contributions to this work. We are also grateful to agencies NIH, NSF, WHO, CDC as well as the Li Foundation,

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