Prior killing of intracellular bacteria Wolbachia reduces inflammatory reactions and improves antifilarial efficacy of diethylcarbamazine in rodent model of Brugia malayi

Abstract

The discovery of the endosymbiont Wolbachia, which has a mutualistic relationship with filarial nematodes, and its importance in filarial parasite biology has provided a lead for developing novel chemotherapeutic agents against human filariasis. Wolbachia also appears to be involved in immunopathological responses as well as adverse reactions after antifilarial therapy. The aim of the present study was to explore the potential of administering anti-Wolbachial therapy before antifilarial treatment to improve the filaricidal efficacy of the present-day filaricide diethylcarbamazine. An additional objective was to minimize host inflammatory reactions using a rodent model Mastomys coucha and Meriones unguiculatus infected with human lymphatic filariid Brugia malayi. We observed: (1) a 40-day treatment schedule of tetracycline alone resulted in delayed reduction in microfilaraemia and a low degree of macrofilaricidal efficacy; (2) tetracycline therapy followed by 100 mg/kg diethylcarbamazine (DEC) x5 days led to marked reduction in microfilaraemia from day 48 onward after initiation of treatment. The combination treatment also brought about approximately 70% death of adult B. malayi and sterilization of 82.3% of the surviving female worms, thus exhibiting remarkable enhancement in the antifilarial activity of DEC; (3) tissue inflammatory reactions and pathogenesis were significantly reduced as observed by histopathology, and peritoneal macrophage mediated oxidative burst shown by fluorescence-activated cell sorting (FACS) analysis using dichlorofluorescein diacetate (DCF-DA); and (4) the characteristic filarial antigen-specific and mitogen-specific cellular unresponsiveness was significantly reversed, possibly due to marked clearance of microfilaraemia. It is therefore advisable to give an anti-Wolbachial antibiotic trial before starting antifilarial therapy to achieve maximum benefits.

In vitro and in vivo antifilarial potential of marine sponge, Haliclona exigua (Kirkpatrick), against human lymphatic filarial parasite Brugia malayi

“…The antifilarial activity of the crude extract of H. exigua and its fraction in vivo was validated in M. coucha infected with L3 stage of B. malayi. M. coucha infected with subperiodic B. malayi are being used worldwide as an excellent experimental rodent model for evaluating the antifilarial activity of synthetic and natural products (Sänger et al 1981;Zahner et al 1988Zahner et al , 2001aSchares et al 1994;Owais et al 2003;Bajpai et al 2005aBajpai et al , b, 2007Shakya et al 2008). Antifilarial activity (macrofilaricidal and microfilaricidal) of the crude extract and its chloroform fraction was observed on experimental animals at the doses used.…”

Polyanhydride Nanoparticle Delivery Platform Dramatically Enhances Killing of Filarial Worms

“…Discovery of the endosymbiotic bacteria Wolbachia and the critical role they play in the biology and viability of the adult worm revealed a potential target that could be exploited to improve therapies for RB and LF [ 19 , 21 , 42 ]. The addition of anti-bacterials (such as doxycycline or tetracycline) to the treatment regimen can reduce parasite embryogenesis [ 20 , 43 ], improve macrofilaricidal activity, and reduce hydrocele pathology in the host [ 44 , 45 ]. To achieve maximal benefit, daily dosing of 200 mg for 3–5 weeks of antibacterial drug is required and can be a difficult barrier to overcome for Mass Drug Administration (MDA) programs [ 15 , 27 ].…”

Phage WO of Wolbachia: lambda of the endosymbiont world

“…First, vector control programs aimed at curbing the spread of insect-vectored diseases such as malaria and dengue fever will rely on the ability to release insect vectors transfected with Wolbachia infections that reduce the vectorial competence [69-74]. Second, the discoveries that river blindness, lymphatic filariasis [75] and heartworm [76] are associated with Wolbachia -induced pathologies raised the likelihood that antimicrobial therapies targeting Wolbachia may be effective in treatment of the systems [76-79]. For insect diseases, current strategies include (i) using Wolbachia to carry a transgene that would inhibit spread of the infectious agent [80,81], (ii) infecting mosquitoes with a life-shortening strain of Wolbachia so that the insect vector dies before it is capable of transmitting disease [71,82-84], or (iii) releasing Wolbachia -infected males into the wild so that CI will inhibit mosquito reproduction and cause the native populations to crash to less-threatening levels [85,86].…”