New Frontiers: Wolbachia


Great fleas have little fleas upon their backs to bite 'em
And little flease have lesser fleas, and so ad infinitum.
- Augustus de Morgan

For many years it has been known that filarial nematodes, including O. volvulus, harbor endosymbiotic bacteria. The bacteria, part of the genus Wolbachia, seem to have an extremely old mutalistic relationship with their filarial hosts. Wolbachia are located in the hypodermis of male and female worms, the oocytes, embryos and larval stages. They are transmitted vertically between generations via the oocytes similarly to mitochondria. The reason is unknown, but research has shown that fertility of female O. volvulus is dependent on Wolbachia. (18, 58, 59, 69)

Pathology: Not only are O. volvulus and Wolbachia mutually dependent, but many strong connections have been demonstrated between Wolbachia and the immunopathology of onchocerciasis. Neutrophil recruitment is actually caused primarily by the presence Wolbachia; few neutrophils can be found at sites where most bacteria were killed by treatment with the antibiotic doxycycline. The bacterium seems to be an especially important stimulus of the inflammatory response to O.volvulus MF in the eye which results in ocular impairment. The release of Wolbachia from dying MF after treatment with antifilaricides may also be the cause of adverse reactions, for the bacteria induces proinflamatory cytokines responsible for various side effects. (18, 58, 59, 69)

Treatment: Due to the critical role of Wolbachia in the life cycle and disease symptoms of onchocerciasis, drug therapies that target the bacterium may contribute to treatment for O. volvulus. Research has found that tetracycline antibiotics kill the bacteria within the nematode and impact onchcocerciasis in the following important ways:

  • elimination of Wolbachia directly limits the bacteria induced immunopathology of Onchocerciasis thus reducing disease symptoms
  • sustained reductions in the level of circulating microfilaria limits MF pathology and reduces transmission
  • sterilization of female worms prevents production of new L1 larva
  • reducing Wolbachia levels prior to administration of Ivermectin or DEC limits negative side effects
  These effects of tetracylines have the potential to play a significant role in the treatment of Onchocerciasis. It has recently been demonstrated that a 6 week regimen of 200mg doxycycline blocks embryogenesis 2 years after start of treatment; this is the longest period of sterility of female worms ever achieved by an antifilarial drug without severe side effects. Employing a combination of tetracycline and antibiotic treatments improves safety of antifilaricides. While the impact on adult worms is limited, it is significant that treatment has demonstrated a macrofilaricidal effect for lymphatic filariasis and bovine onchocerciasis. (18, 58, 59, 69)

Application: While Wolbachia targeted tetracycline treatment has been successfully proven to be an effective therapy for Onchocerciasis, it is not yet a realistic public health treatment. The minimum length of treatment, 4 to 6 weeks, makes mass administration infeasible. In an interview with Patrick Lammie of the CDC, he added that in addition to the cost and logistical difficulties, "we know from clinical experience with use of antibiotics that compliance tends to decrease as the length of treatment increases." (70) This increases the theoretical potential for drug resistance and subsequent increased mortality from bacterial disease that might out way the morbidity of Onchocerciasis. Tetracyclines are also not safe for children under 9 years and women who are pregnant or breastfeeding; prolonged treatment has various negative side effects.

In light of these limitations, treatment is currently recommended on a primarily individual basis for those who will be leaving endemic areas for a long time. Tetracyclines may also be an important component of therapy for O. volvulus strains such as ‘Sowda’ associated with hyper-reactivity, as reduction of Wolbachia prior to treatment may mitigate side effects. Before antibiotics can play a bigger role in Onchocerciasis control, more research is needed into shorter course therapies and new Wolbachia specific drugs. (18, 58, 59, 69)

For more information see interview with expert Patrick Lammie