Wolbachia Bacteria and Biocontrol of Arboviral Diseases

Arboviruses (arthropod-borne viruses) are transmitted by arthropod vectors such as mosquitoes and ticks and cause significantly human morbidity and mortality. There are more than 80 different arboviruses that are known human pathogens with dengue virus (DENV) having the greatest impact on humans. DENV is within the genus Flavivirus that also includes medically important viruses such as West Nile virus (WNV), Yellow fever virus (YFV) and Japanese encephalitis virus (JEV) that are transmitted by mosquitoes. Estimates of annual global DENV infections range from 100–390 million, with 100 million symptomatic infections leading to 12,500 deaths per year. The resulting disease, dengue fever, is classified as 're-emerging' predominantly because the range of the principal mosquito vector, Stegomyia (Aedes) aegypti), is increasing alongside the secondary vector Stegomyia (Aedes) albopictus. The range of these two invasive mosquito species is expanding due to several factors including globalization and climate change. Dengue outbreaks typically occur in tropical areas of Southeast Asia and South America in countries where disease has a significant impact on struggling economies. Early recognition and supportive treatment can help lower the risk of severe morbidity or mortality although diagnosis is often difficult in developing countries. Mosquito vector control has been the only way to prevent transmission, as there are currently no vaccines or drugs available for dengue. Successful mosquito control for dengue has been problematic for several reasons. Stegomyia aegypti are anthropophilic mosquitoes (preferring to bite humans) and are extremely well adapted to living in urban environments in close proximity to dense human populations. This species of mosquito has a preference for laying eggs in artificial containers (e.g. Water tanks and unused tires) so widespread larval source reduction is difficult to implement. Another widely used method has been outdoor spraying of insecticides such as DDT and malathion. Singapore is a good example of how dengue continues to persist even with a strictly implemented vector control program. Dengue was first reported in 1960 and government interventions through integrated mosquito control programs reduced the incidence of transmission by the 1970s. However, Singapore has recently seen resurgence in dengue cases despite a significant control program targeting mosquitoes. If a country like Singapore is unable to prevent dengue transmission, current vector control methods are clearly not working and novel methods need to be developed. The options for developing new technologies for mosquito control fall into two major strategies. Population suppression aims to reduce or eliminate the wild mosquito population. Examples of this include conventional methods such as insecticides and larval source reduction. A novel suppression strategy that is showing potential has been the generation of genetically modified mosquitoes that can be released to 'crash' the existing wild population. The British biotech company Oxitec is currently working in dengue endemic countries such as Brazil with a strain of mosquito that they are hoping can achieve population reduction or even elimination. Oxitec has genetically modified Stegomyia mosquitoes to create sterile males that are then released to mate with wild females. The resulting progeny inherit a 'lethal gene' and do not survive to adulthood. Oxitec is able to rear the mosquitoes in insectaries by providing a repressor (the antibiotic tetracycline) in the diet that prevents lethal effects. This approach has the advantage of being very species-specific and has no long lasting effects on the target species, as the aim is to eliminate the population in the release area. Critics of this strategy would question the cost-effectiveness as repeated releases may be required if re-immigration of mosquitoes into the release area occurs. However, a larger issue for Oxitec's approach has been the concern regarding releasing genetically modified ('GM') insects despite many studies showing this approach is unlikely to have any major negative effects on the environment. An alternative approach is to replace the wild mosquito population with mosquitoes that are unable to transmit disease. Genetically modified mosquitoes that are 'refractory' to DENV transmission have been developed. However, concerns over the effects of GM on mosquito fitness, crucial if releasing to compete with wild mosquitoes, has prevented any large-scale trials. A novel approach that has the potential to be very effective is the use of endosymbiotic bacteria to prevent DENV from replicating within the mosquito. In recent years, Wolbachia-based biocontrol has emerged as a very promising method that is environmentally friendly, safe to humans and potentially cost effective. The 'eliminate dengue' project based in Australia has been able to demonstrate that Wolbachia bacteria can prevent DENV transmission in mosquitoes without significant fitness costs.