Wolbachia :: drug effects
Latest Paper:
Jeffrey Gilbert,
Charles K Nfon,
Benjamin L Makepeace,
Leo M Njongmeta,
Ian M Hastings,
Kenneth M Pfarr,
Alfons Renz,
Vincent N Tanya,
Alexander J Trees
Liverpool School of Tropical Medicine and Faculty of Veterinary Science, University of Liverpool, United Kingdom.
Development of a drug lethal to adult Onchocerca volvulus (i.e., macrofilaricide) is a research priority for the control of human onchocerciasis. Using bovine O. ochengi infections, we investigated the effects of oxytetracycline administered in a short intensive regimen (SIR; 10 mg/kg daily for 14 days), compared with a prolonged intermittent regimen (PIR; 20 mg/kg monthly for 6 months) or a combination of both (COM), on the viability of adult worms and their endosymbiotic bacteria (Wolbachia species). The long-term treatments eliminated >80% (COM) or >60%(PIR) of adult female worms (P<.001), and the COM regimen effected a sustained depletion of Wolbachia organisms. Conversely, SIR was not macrofilaricidal and only transiently depleted Wolbachia densities, which repopulated worm tissues by 24 weeks after treatment. These results unequivocally demonstrate the macrofilaricidal potential of tetracyclines against Onchocerca infection and suggest that intermittent, protracted administration will be more effective than continuous shorter term treatment.
Mesh-terms: Animals; Cattle; Cattle Diseases :: drug therapy; Cattle Diseases :: immunology; Cattle Diseases :: parasitology; Disease Models, Animal; Onchocerca :: microbiology; Onchocerciasis :: drug therapy; Onchocerciasis :: veterinary; Research Support, Non-U.S. Gov't; Symbiosis :: drug effects; Tetracyclines :: pharmacology; Tetracyclines :: therapeutic use; Wolbachia :: drug effects; Wolbachia :: physiology;
Most cited papers:
Endosymbiotic bacteria living in plasmodia or worm parasites are required for the homoeostasis of their host and should be excellent targets for chemotherapy of certain parasitic diseases. We show that targeting of Wolbachia spp bacteria in Onchocerca volvulus filariae by doxycycline leads to sterility of adult worms to an extent not seen with drugs used against onchocerciasis, a leading cause of blindness in African countries.
Mesh-terms: Adolescent; Adult; Animals; Anti-Bacterial Agents :: pharmacology; Anti-Bacterial Agents :: therapeutic use; DNA, Bacterial :: analysis; DNA, Helminth :: analysis; Doxycycline :: pharmacology; Doxycycline :: therapeutic use; Female; Human; Male; Middle Aged; Onchocerca volvulus :: genetics; Onchocerca volvulus :: microbiology; Onchocerciasis :: drug therapy; Onchocerciasis :: microbiology; Polymerase Chain Reaction; Support, Non-U.S. Gov't; Symbiosis; Wolbachia :: drug effects; Wolbachia :: genetics; Wolbachia :: physiology;
N G Langworthy,
A Renz,
U Mackenstedt,
K Henkle-Dührsen,
M B de Bronsvoort,
V N Tanya,
M J Donnelly,
A J Trees
Liverpool School of Tropical Medicine and Faculty of Veterinary Science, University of Liverpool, UK.
Filarial nematodes are important and widespread parasites of animals and humans. We have been using the African bovine parasite Onchocerca ochengi as a chemotherapeutic model for O. volvulus, the causal organism of 'river blindness' in humans, for which there is no safe and effective drug lethal to adult worms. Here we report that the antibiotic, oxytetracycline is macrofilaricidal against O. ochengi. In a controlled trial in Cameroon, all adult worms (as well as microfilariae) were killed, and O. ochengi intradermal nodules resolved, by nine months' post-treatment in cattle treated intermittently for six months. Adult worms removed from concurrent controls remained fully viable and reproductively active. By serial electron-microscopic examination, the macrofilaricidal effects were related to the elimination of intracellular micro-organisms, initially abundant. Analysis of a fragment of the 16S rRNA gene from the O. ochengi micro-organisms confirmed them to be Wolbachia organisms of the order Rickettsiales, and showed that the sequence differed in only one nucleotide in 858 from the homologous sequence of the Wolbachia organisms of O. volvulus. These data are, to our knowledge, the first to show that antibiotic therapy can be lethal to adult filariae. They suggest that tetracycline therapy is likely to be macrofilaricidal against O. volvulus infections in humans and, since similar Wolbachia organisms occur in a number of other filarial nematodes, against those infections too. In that the elimination of Wolbachia preceded the resolution of the filarial infections, they suggest that in O. ochengi at least, the Wolbachia organisms play an essential role in the biology and metabolism of the filarial worm.
Mesh-terms: Animals; Cameroon; Cattle; Female; Human; Male; Onchocerca :: cytology; Onchocerca :: drug effects; Onchocerca :: microbiology; Onchocerciasis :: drug therapy; Onchocerciasis, Ocular :: parasitology; Oxytetracycline :: pharmacology; Oxytetracycline :: therapeutic use; Support, Non-U.S. Gov't; Tetracyclines :: pharmacology; Tetracyclines :: therapeutic use; Wolbachia :: drug effects; Wolbachia :: physiology;
Department of Public Health, Erasmus MC, University Medical Centre Rotterdam, 3000 DR Rotterdam, Netherlands. w.stolk@erasmusmc.nl
BACKGROUND: Wolbachia endosymbionts of filarial nematodes are vital for larval development and adult-worm fertility and viability. This essential dependency on the bacterium for survival of the parasites has provided a new approach to treat filariasis with antibiotics. We used this strategy to investigate the effects of doxycycline treatment on the major cause of lymphatic filariasis, Wuchereria bancrofti. METHODS: We undertook a double-blind, randomised, placebo-controlled field trial of doxycycline (200 mg per day) for 8 weeks in 72 individuals infected with W bancrofti from Kimang'a village, Pangani, Tanzania. Participants were randomly assigned by block randomisation to receive capsules of doxycycline (n=34) or placebo (n=38). We assessed treatment efficacy by monitoring microfilaraemia, antigenaemia, and ultrasound detection of adult worms. Follow-up assessments were done at 5, 8, 11, and 14 months after the start of treatment. Analysis was per protocol. FINDINGS: One person from the doxycycline group died from HIV infection. Five (doxycycline) and 11 (placebo) individuals were absent at the time of ultrasound analysis. Doxycycline treatment almost completely eliminated microfilaraemia at 8-14 months' follow-up (for all timepoints p< .001). Ultrasonography detected adult worms in only six (22%) of 27 individuals treated with doxycycline compared with 24 (88%) of 27 with placebo at 14 months after the start of treatment (p< .0001). At the same timepoint, filarial antigenaemia in the doxycycline group fell to about half of that before treatment (p= .015). Adverse events were few and mild. INTERPRETATION: An 8-week course of doxycycline is a safe and well-tolerated treatment for lymphatic filariasis with significant activity against adult worms and microfilaraemia.
Mesh-terms: Adolescent; Adult; Aged; Animals; Anti-Bacterial Agents :: therapeutic use; Double-Blind Method; Doxycycline :: therapeutic use; Elephantiasis, Filarial :: drug therapy; Elephantiasis, Filarial :: parasitology; Humans; Male; Middle Aged; Research Support, Non-U.S. Gov't; Wolbachia :: drug effects; Wuchereria bancrofti :: drug effects; Wuchereria bancrofti :: microbiology;
Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Patologia, Generale e Parassitologia, Università di Milano, 20133 Milan, Italy.
The presence of intracellular bacteria in the body of various species of filarial nematodes, including important parasites such as Brugia malayi, Dirofilaria immitis, and Onchocerca volvulus, was observed as early as the mid-1970s. These bacteria were shown to be transovarially transmitted (from the female worm to the offspring) and to be present in significant amounts in the body of the nematode. As highlighted by their discoverers, the potential importance of these bacteria is fairly obvious:(1) bacteria-derived molecules should be considered as having an immunological and pathological role in filarial diseases;(2) the interaction between the bacteria and the filarial host deserves investigation, in view of the possibility that the bacteria are needed by the host nematode and could thus represent a target for therapy. Other authors, independently from the discovery of these intracellular bacteria, showed that the antibiotic tetracycline (which is well known for its efficacy on intracellular bacteria) had detrimental effects on two species of filarial nematodes (Brugia pahangi and Litomosoides sigmodontis). It is therefore surprising that for more than 20 years, no further investigations focused on the bacteria of filarial nematodes, nor on the anti-filarial properties of tetracycline. Recently, the bacteria of filarial nematodes have been independently "rediscovered" by research groups from the schools of Hamburg, Liverpool and Milan. These bacteria are now classified as Wolbachia, and the basic aspects of their phylogenetic history and relationship with the Wolbachia of arthropods have been reconstructed. In addition, their implications for the pathogenesis and treatment of filarial diseases have started to be uncovered. This paper, which is authored by representatives of the three European schools who reopened this research area, reviews our present knowledge of these fascinating microorganisms, highlighting the complexity of a symbiotic system which involves, in addition to the nematode and its bacterium, the vertebrate host.
Mesh-terms: Animals; Anthelmintics :: adverse effects; Anthelmintics :: therapeutic use; Anti-Bacterial Agents :: therapeutic use; Antibodies, Bacterial :: analysis; Antibodies, Bacterial :: biosynthesis; Diethylcarbamazine :: adverse effects; Diethylcarbamazine :: therapeutic use; Evolution; Filariasis :: drug therapy; Filariasis :: microbiology; Filariasis :: parasitology; Filarioidea :: microbiology; Human; Phylogeny; Support, Non-U.S. Gov't; Symbiosis; Wolbachia :: drug effects; Wolbachia :: genetics; Wolbachia :: growth & development;
The symbiosis of filarial nematodes and intracellular Wolbachia bacteria has recently been exploited as a target for antibiotic therapy of filariasis. Antibiotic treatment of filarial nematodes results in sterility and inhibits larval development and adult worm viability. In the first trial on human onchocerciasis depletion of bacteria following treatment with doxycycline resulted in a complete and long-term block of embryogenesis. Bacteria are unable to repopulate nematode tissues up to 18 months after depletion, suggesting these effects may be permanent. Following ivermectin treatment, individuals given antibiotic therapy showed sustained reductions in skin microfilariae, with the majority of people remaining microfilarial negative 12-18 months after treatment. Since Wolbachia also contribute to the inflammatory pathogenesis of filarial disease, antibiotic therapy could, in addition to effects on worm fertility or viability, prevent the onset or development of filarial pathology.
Department of Biology, University College London, London NW1 2HE, United Kingdom. g.hurst@galton.ucl.ac.uk
Inherited microorganisms that disturb the reproduction of their host have been characterized from a number of host taxa. To understand the general principles underlying the genetic and mechanistic basis of interactions, study of different agents in model host species is required. To this end, the nature and genetics of the maternally inherited sex-ratio trait of Drosophila bifasciata were investigated. Successful curing of affected lines with antibiotics demonstrated this trait was associated with the presence of a bacterium, and molecular systematic analysis demonstrated an association between the presence of the trait and infection with an A group Wolbachia. The penetrance and heritability of the trait did not vary with maternal age. Exposure to elevated temperatures did reduce trait penetrance but did not affect heritability. Examination of the effect of temperature on bacterial density in eggs revealed a decrease in bacterial density following exposure of the parent to elevated temperature, consistent with the hypothesis that male killing in D. bifasciata requires a threshold density of Wolbachia within eggs. The male offspring produced following exposure to elevated temperatures were infected with Wolbachia on emergence as adults. Crossing studies demonstrated a weak cytoplasmic incompatibility phenotype exhibited by Wolbachia in these males. The results are discussed with respect to the incidence of male killing within the clade Wolbachia, the general nature of Wolbachia-host interactions, and the prospects for using this association to investigate the mechanism of male killing.
Mesh-terms: Animals; Crosses, Genetic; Drosophila :: classification; Drosophila :: genetics; Drosophila :: microbiology; Female; Fertility; Larva; Male; Phenotype; Phylogeny; Rifampin :: pharmacology; Sex Ratio; Support, Non-U.S. Gov't; Temperature; Wolbachia :: drug effects; Wolbachia :: growth & development; Wolbachia :: pathogenicity;
Department of Helminthology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. hoerauf@bni.uni-hamburg.de
More effective drugs are needed for the treatment of human filarial diseases and the elimination of these infections as a public health problem. The drugs must either kill or sterilize adult worms. The relevant filariae, Onchocerca volvulus, Wuchereria bancofti and Brugia species, harbor rickettsial endoboacteria of the genus Wolbachia as symbionts. Animal experiments have shown that the elimination of these endobacteria causes inhibition of embryogenesis, and with Onchocerca ochengi a macrofilaricidal effect. Trials with human onchocerciasis patients using doxycydine demonstrated a long-term sterilizing activity, opening up a new strategy for the control of filarial infections. Indications of antiwolbachial therapy against onchocerciasis are discussed.
Mesh-terms: Animals; Brugia :: microbiology; Doxycycline :: administration & dosage; Doxycycline :: therapeutic use; Drug Resistance; Filariasis :: drug therapy; Filariasis :: parasitology; Filaricides :: therapeutic use; Human; Onchocerca :: microbiology; Onchocerciasis :: drug therapy; Onchocerciasis :: parasitology; Support, Non-U.S. Gov't; Symbiosis; Wolbachia :: drug effects; Wuchereria bancrofti :: microbiology;
Department of Helminthology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. lars_volkmann@hotmail.com
The symbiosis of filarial nematodes and rickettsial Wolbachia endobacteria has been exploited as a target for antibiotic therapy of filariasis. Depletion of Wolbachia after tetracycline treatment results in filarial sterility because of interruption of embryogenesis and inhibits larval development and adult worm viability. The aim of this study was to investigate if antibiotic intervention of BALB/c mice infected with the rodent filaria Litomosoides sigmodontis with rifampicin or the combination of rifampicin and doxycycline can be used to shorten the treatment period. Both regimens, when given over a period of 14 days initiated with infection, were sufficient to deplete Wolbachia as evidenced by immunohistology and semiquantitative PCR. Worm development and filarial load were significantly reduced in experiments followed up until 63 days p.i. The therapy inhibited embryogenesis and led to filarial sterility. In contrast, treatment with doxycycline alone for 21 days led only to a modest reduction of Wolbachia, filarial growth retardation, worm viability and fertility. In conclusion, the combination of antirickettsial drugs could be used as a suitable tool to explore the minimum duration of therapy required for the depletion of Wolbachia in parasitized hosts subsequent to the onset of patency in human and animal filariasis and the prevention of adverse reactions in human infections.
Mesh-terms: Animals; Anti-Bacterial Agents :: therapeutic use; Antibiotics, Combined :: therapeutic use; Comparative Study; Doxycycline :: therapeutic use; Female; Filariasis :: complications; Filariasis :: drug therapy; Filariasis :: pathology; Filarioidea :: drug effects; Filarioidea :: growth & development; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration :: drug effects; Polymerase Chain Reaction; Rickettsiaceae Infections :: complications; Rickettsiaceae Infections :: drug therapy; Rickettsiaceae Infections :: pathology; Rifampin :: therapeutic use; Support, Non-U.S. Gov't; Symbiosis :: drug effects; Wolbachia :: drug effects; Wolbachia :: growth & development;
Department of Systems Science (Biology), and Department of Biological Science at the Graduate School of Arts and Sciences, University of Tokyo, Meguro, Tokyo 153-8902, Japan. t-fukatsu@aist.go.jp
The adzuki bean beetle, Callosobruchus chinensis, is triple-infected with distinct lineages of Wolbachia endosymbiont, wBruCon, wBruOri, and wBruAus, which were identified by their wsp (Wolbachia surface protein) gene sequences. Whereas wBruCon and wBruOri caused cytoplasmic incompatibility of the host insect, wBruAus did not. Although wBruCon and wBruOri were easily eliminated by antibiotic treatments, wBruAus persisted over five treated generations and could not be eliminated. The inheritance pattern of wBruAus was, surprisingly, explained by sex-linked inheritance in male-heterozygotic organisms, which agreed with the karyotype of C. chinensis (2n = 20, XY). Quantitative PCR analysis demonstrated that females contain around twice as much wsp titer as males, which is concordant with an X chromosome linkage. Specific PCR and Southern blot analyses indicated that the wBruAus-bearing strain of C. chinensis contains only a fraction of the Wolbachia gene repertoire. Several genome fragments of wBruAus were isolated using an inverse PCR technique. The fragments exhibited a bacterial genome structure containing a number of ORFs typical of the alpha-proteobacteria, although some of the ORFs contained disruptive mutations. In the flanking region of ftsZ gene, a non-long terminal repeat (non-LTR) retrotransposon sequence, which is typical of insects but not found from bacteria, was present. These results strongly suggest that wBruAus has no microbial entity but is a genome fragment of Wolbachia endosymbiont transferred to the X chromosome of the host insect.
Mesh-terms: Animals; Base Sequence; Beetles :: genetics; Blotting, Southern :: methods; DNA, Bacterial; Drosophila melanogaster :: microbiology; Drug Resistance, Bacterial; Evolution, Molecular; Female; Gene Transfer, Horizontal; Genes, Bacterial; Genome, Bacterial; Male; Molecular Sequence Data; Polymerase Chain Reaction :: methods; Research Support, Non-U.S. Gov't; Rifampin :: pharmacology; Symbiosis; Tetracycline :: pharmacology; Wolbachia :: drug effects; Wolbachia :: genetics; Wolbachia :: isolation & purification; X Chromosome;
Wolbachia density and host fitness components in Muscidifurax uniraptor (Hymenoptera: pteromalidae).
Department of Entomology, The Hebrew University of Jerusalem, Rehovot, 76100, Israel.
Intracellular bacteria of the genus Wolbachia are found in a variety of arthropod hosts, where they cause various reproductive disorders. Attempts to study the fitness advantages and disadvantages of carrying these symbionts have yielded contradicting results. Using various doses of the antibiotic rifampicin, we were able to manipulate the density of Wolbachia in the uniparental parasitoid Muscidifurax uniraptor (Hymenoptera: Pteromalidae). The effect of different titers of the symbiont on the fecundity, reproductive rate, longevity, survival rate, and sex ratio of the host was measured. The data gathered show that following antibiotic treatments, the percentage of males rises at low doses of rifampicin and then drops again. The total sex ratio of offspring produced by treated mothers was positively correlated with the numbers of Wolbachia found in eggs laid by these females. No significant effects were detected with regard to the other studied fitness components. It is concluded that in M. uniraptor, Wolbachia are not posing any burden on the life history trait studied.
Mesh-terms: Animals; Anti-Bacterial Agents :: pharmacology; Colony Count, Microbial; Hymenoptera :: drug effects; Hymenoptera :: microbiology; Reproduction :: drug effects; Rifampin :: pharmacology; Sex Ratio; Support, Non-U.S. Gov't; Wolbachia :: drug effects; Wolbachia :: isolation & purification;
