Interactions among multiple genomes: Tsetse, its symbionts and trypanosomes

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Abstract

Insect-borne diseases exact a high public health burden and have a devastating impact on livestock and agriculture. To date, control has proved to be exceedingly difficult. One such disease that has plagued sub-Saharan Africa is caused by the protozoan African trypanosomes (Trypanosoma species) and transmitted by tsetse flies (Diptera: Glossinidae). This presentation describes the biology of the tsetse fly and its interactions with trypanosomes as well as its symbionts. Tsetse can harbor up to three distinct microbial symbionts, including two enterics (Wigglesworthia glossinidia and Sodalis glossinidius) as well as facultative Wolbachia infections, which influence host physiology. Recent investigations into the genome of the obligate symbiont Wigglesworthia have revealed characteristics indicative of its long co-evolutionary history with the tsetse host species. Comparative analysis of the commensal-like Sodalis with free-living enterics provides examples of adaptations to the host environment (physiology and ecology), reflecting genomic tailoring events during the process of transitioning into a symbiotic lifestyle. From an applied perspective, the extensive knowledge accumulated on the genomic and developmental biology of the symbionts coupled with our ability to both express foreign genes in these microbes in vitro and repopulate tsetse midguts with these engineered microbes now provides a means to interfere with the host physiological traits which contribute to vector competence promising a novel tool for disease management.

Introduction

Tsetse flies (Diptera: Glossinidae) are the sole vectors of cyclical pathogenic trypanosomes in tropical Africa. Human African trypanosomiasis (HAT), or sleeping sickness, is a zoonosis caused by the flagellated protozoan Trypanosoma brucei rhodesiense in East and southern Africa and T. b. gambiense in West and Central Africa. It is conservatively estimated by the World Health Organization (WHO, 2001) that there are currently 300,000–500,000 cases of HAT with 60 million people at risk in 37 countries covering approximately 40% of Africa (11 M km2). After a devastating epidemic in the early 20th century when a million people died of HAT, the disease almost disappeared from Africa by the 1960s following eradication campaigns, mostly based on insecticide applications. But we are currently in the midst of another HAT epidemic with a high disease burden of 2.05 M disability-adjusted life years (Ekwanzala et al., 1996; Moore et al., 1999; van Hove, 1996). The countries in Central Africa, especially the Democratic Republic of Congo (DRC), Angola and Southern Sudan, are countries which have been the hardest hit while Uganda is under threat with sporadic infections reported. The rate of new infections and mortality (55,000 deaths in 1993; 66,000 in 1999) shows no sign of decline. The collapse of health infrastructures and surveillance systems (Simarro et al., 2003), allied to the displacement of populations by war and natural disaster, are important contributory factors to the present epidemic. Given that the disease affects hard-to-reach rural populations, which lack active surveillance in the war-torn areas, it is not surprising that the disease prevalence estimates are generally considered a gross underestimation. The consensus view is that the situation may worsen (Barrett, 1999; Smith et al., 1998; Stich et al., 2003). In addition to their importance to human health, trypanosomes cause a wasting and fatal disease in cattle, domestic pigs and other farm animals known as nagana. Nagana is caused by the related parasites, T. b. brucei, T. congolense and T. vivax and has restricted agricultural development and nutritional resources in sub-Saharan Africa profoundly impacting the economy of much of the continent (Jordan, 1986; Steelman, 1976).

The prevalence of trypanosomiasis relies on four interacting organisms: the human host, the insect vector, the pathogenic parasite and the domestic and wild animal reservoirs. While complex, this dependence on multiple players provides several opportunities for intervention since interruption of any of these interactions can potentially reduce disease transmission. Despite extensive research on African trypanosomes in pursuit of vaccine candidates for the immunization of humans and cattle, antigenic variation of surface glycoproteins while in the mammalian host has hampered most efforts. Moreover, there are no effective vaccine candidates forthcoming for disease control in the foreseeable future. The current management of HAT has relied on the extensive involvement of international organizations and relies on active surveillance and treatment of infected patients. These efforts have been constrained by the lack of inexpensive, easy to administer and effective drugs (Butler, 2003; Docampo and Moreno, 2003). In addition, the efficacy of available drugs has been impaired due to increasing resistance by the parasites (Anene et al., 2001; Geerts et al., 2001). The soon to be completed genome sequence of the parasite now provides the impetus for the identification of new potential targets of attack (El-Sayed et al., 2003). Nevertheless, strategic difficulties in accessing the rural populations inflicted with this disease, the lack of sensitive diagnostic tools and the presence of extensive wild animal reservoirs for the parasite will continue to threaten the long-term success of chemotherapy as the gold-standard for control of this particular disease.

Section snippets

Tsetse—vector of African trypanosomes

Tsetse flies, both the blood-feeding males and females, are the sole vectors of human-infective African trypanosomes. The major human disease vectors are species of the palpalis complex, involved in transmission of T. b. gambiense in Central and West Africa and T. b. rhodesiense in East Africa, although flies of the morsitans complex also contribute to significant human disease transmission (recently reviewed in Aksoy et al., 2003). For T. b. rhodesiense, the presence of domestic and wild

Symbiosis in tsetse

Arthropods, in particular, owe much of their ecological success to resident microbial flora that often provide nutrients either lacking in their limited diet or which the hosts are incapable of synthesizing (Table 1). Symbiotic associations allow the hosts to exploit unique or restricted ecological niches that would otherwise be impractical to inhabit. Symbionts with obligate functions in host biology have been termed primary (P)-symbionts, while the more recently established commensal-like

Symbiont transformation technology

Although the microaerophilic nature of many gut symbionts has hampered their cultivation from animals, Sodalis has been successfully cultivated in vitro (Welburn et al., 1987; Beard et al., 1993). The availability of an in vitro culture system has enabled the development of a genetic transformation system to introduce and express foreign products in Sodalis (Beard et al., 1993) and, in turn in their host insects, an approach called paratransgenesis (Aksoy, 2001; Aksoy, 2003; Aksoy et al., 2001;

Gene-driving systems—Wolbachia-mediated cytoplasmic incompatability

An important applied aspect of all transgenic approaches is the ability to spread the laboratory-engineered phenotypes into natural populations. The Wolbachia symbiont which has infected a wide range of invertebrate hosts (Werren et al., 1995), including several tsetse species, provides one potential drive mechanism. One of the unique functions of Wolbachia, termed cytoplasmic incompatibility (CI), results in death early in embryogenesis. In an incompatible cross, the sperm enters the egg but

Conclusions and future directions

Extensive knowledge accumulated on tsetse and its symbionts now provides unique disease management opportunities based on the control of parasite development in its invertebrate host. Both symbionts Wigglesworthia and Sodalis display genomic traits reflective of their dependencies on their host biology. Their close proximity to the developing trypanosomes in the gut, the ease of prokaryotic transformation systems and gene expression, as well as the soon available genome sequence information

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, Youjia Hu, Irene Kasumba, Dana Nayduch, Brian Weiss, Douglas Smith and Patricia M. Strickler and to colleagues Masahira Hattori, Hidemi Watanabe, Atsushi Yamashita and Hattori Toh for their contributions to this work. We are grateful to the agencies NIH/NIAID, NSF, WHO as well as to the Li Foundation and MacKnight Foundation, Robert Leet and Clara Gutherie

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