RESEARCH NEWS CURRENT SCIENCE, VOL. 80, NO. 5, 10 MARCH 2001 614 Wolbachia: Potential targets for control of filariases B. P. Mohanty Filariae are responsible for devastating diseases in man, including blindness (onchocerciasis) and elephantiasis (lym- phatic filariasis), with 150 million infec- tions worldwide 1 . Onchocerciasis is mainly restricted to Africa (inhabits 99% of the infected people) 2 , whereas lym- phatic filariasis (LF) is widespread and is a major cause of clinical morbidity of humans in the tropics and subtropics, afflicting over 120 million people worldwide 3 . Further, more than 1.1 thou- sand million people (20% of the world’s population) now live in areas where they are at the risk of infection 2 . India alone accounts for 40% of the global preva- lence of infection 4 . LF is caused by the blood-borne fila- rial parasites Wuchereria bancrofti, Brugia malayi and B. timori. These fila- rial parasites have a complex life cycle and require a mosquito vector for trans- mission. Infection is initiated by the infective third-stage larvae (L3) via the bite of an infected mosquito. The L3 then migrate to the lymphatics and develop through two further moults to become adult worms (commonly named macro- filariae); following mating the adult female produces an abundance of micro- filaria (Mf or Larvae 1) which circulate in the blood stream of the infected host. When ingested by a susceptible mos- quito, the Mf migrate to the thoracic muscles and develop through further two moults to become L3, which are trans- mitted to a new host when the infected mosquito next takes a blood meal 5 . The world community has made it a goal to interrupt transmission and elimi- nate LF globally as a public health prob- lem by the year 2020, in accordance with resolution WHA50.29 of the Fiftieth World Health Assembly 2,3 . Similarly, the elimination of onchocerciasis as a public health problem in 11 west African coun- tries has been targeted by 2002 (ref. 2). Therefore, control programmes have been launched worldwide with an emphasis on community-wide treatment. The present antifilarias like diethylcarbamazine (DEC), ivermectin and albendazole are mainly targeted at mature Mf and have low macrofilaricidal activity 3,6,7 . Many of the adult parasites, therefore, survive after the chemotherapy and lead to reappea- rance of Mf several months after treat- ment. Thus, there is a pressing need for new antifilarial drugs that have macro- filaricidal efficacy and/or that show total and long-lasting suppression of embryo production, to complement currently available microfilaricides. Under these circumstances, Wolbachia, the bacterial endosymbiont of the filarial parasites, show great promise as targeting of these bacteria might offer a novel alternative that could have effects on both adult worms and Mf. What is Wolbachia? Wolbachia is a group of intracellular bacteria, discovered in the seventies 8–11 with the advent of electron microscopy. They belong to the order Rickettsiales and are closely related to the genera Ehr- lichia, Cowdria and Anaplasma 12 . They are widespread in the arthropods and important insect pests as well as disease vectors. They are also present in filarial nematodes 13 . It was speculated that these bacteria might be related to the Wolba- chia symbionts of vector insects and might contribute to the pathogenesis of filarial disease and offer a novel target for chemotherapy 8–11 . However, this fascinating symbiosis between the filarial nematodes and Wolbachia remained ignored for a long time, until later identi- fied in the dog heart worm, Dirofilaria immitis, as a close relative of Wolbachia complex 14 . Wolbachia have been detected in majority of filarial species analysed so far, (including the major human filarial parasites W. bancrofti, B. malayi and Onchocerca volvulus) 11,15 ; however, the rodent filaria Acanthochelonema vitae 16 and the deer parasite O. flexuosa 17,18 are devoid of these bacteria. Recently, the bacteria have been visualized by immu- nohistology using antibodies against bacterial catalase 17 and heat shock pro- tein 60 (hsp60) 19 . The bacteria are wide- spread in female worms than males and the principal mode of transmission is via the eggs of females 15 . Phylogenetic analysis has shown that all filarial Wolbachia are closely related and in general form a group separate from Wolbachia of arthropods 15 . The phylogenetic patterns suggest a long coevolutionary history and reciprocal coadaptation between filarial worms and their Wolbachia symbionts. Further, treatment with bacteriostatic drug – tetracycline has been shown to inhibit reproduction and development in filarial nematodes harbouring Wolbachia. Thus studies support the possibility that Wol- bachia is necessary to the host nematode and it seems to play an important role in the development, viability and fertility of filarial nematodes; however, the mole- cular basis of these interactions is unknown 12 . Having remained dormant for about 25 years since their discovery, these bacteria have emerged in an ‘epi- demic’ throughout the filarial research community. The central question now is how the mutualistic symbiotic association between this bacteria and its filarial nematode host can be exploited to control this debilitating and disfiguring disease. Wolbachia in the pathogenesis of filarial disease The pathogenesis of filarial disease is characterized by acute and chronic inflammation. Inflammatory responses are thought to be generated either by the parasite, the immune response or oppor- tunistic infection 15 . The presence of large number of bacteria in the parasite tissues in a variety of developmental stages sug- gests that, either on death of the parasite or through a variety of secretory/excre- tory mechanisms, the release of bacteria and/or their products might contribute to the inflammatory pathology associated with human filarial disease. The most direct situation in which death of para- sites leads to inflammatory responses is in the adverse reaction to chemotherapy. The increase in proinflammatory cyto- kines and inflammatory mediators fol- lowing treatment and the clinical presentation of fever, headache, lethargy hypotension and so on, bear many simi- RESEARCH NEWS