Wolbachia is intracellular bacteria that are commonly found in nematodes and arthropods. They are transmitted vertically via host eggs and transforms host biology in diverse ways. In arthropods, Wolbachia infection is linked to the alteration in host reproduction, which includes induction of parthenogenesis, killing of male embryos, cytoplasmic incompatibility (CI) and feminization of genetic males. Some of the methods used to remove them from worms include antibiotics, temperature treatment and rearing host under crowded conditions. The common antibiotics used to eliminate Wolbachia from their definitive hosts include Oxytetracycline, Rifampicin, Doxycycline, Penicillin and Ciprofloxacin. The discovered side effects of using antibiotics to remove Wolbachia include sterility/ infertility/oogenesis inhibition, loss of motility, sexual mosaic and death of worms. Several scholars and entities have continued to study the impact of Wolbachia in arthropods and nematodes responsible for disease or infection in domestic animals. Most of these studies have been underlined by the use of animal infection as a model for exploring the side effects of antibiotic treatment on worm survival and fecundity. Similarly, other studies have focused on role of Wolbachia in the immune response, pathogenesis and diagnosis of the infection or diseases they cause in the definite host. The search for possible effects of post-antibiotic use to eliminate Wolbachia is of primary importance to the status of knowledge on Wolbachia, and veterinary medicine will be discussed in this paper too. The discussion presented in this paper may contribute to future innovative studies and advances in biological vector analyses, especially on the therapeutic advantages of antibiotic treatments designed to eliminate Wolbachia load in adult worms.
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Possible Side Effects after the Use of Antibiotics to Eliminate Wolbachia
Introduction
Wolbachia was discovered in 1924, and later described in 1936 by Hertig and Wolbach. Itis a member of the Alphaproteobacteria (?-Proteobacteria) endosymbionts (Brenner, Krieg, & Staley, 2005; Pike & Kingcombe, 2009). Brenner, Krieg, and Staley (2005) describes Wolbachia pipientis as the sole species of the genus Wolbachia.Moreover, Wolbachia are intracellular bacteria that are commonly found in nematodes and arthropods. Wolbachia multiplies by binary fission within the vacuoles of host cells, but surrounded by a membrane from the host origin. In arthropods, Wolbachia is mainly present in the cytoplasm of the cells within the reproductive organs. However, they can also be observed in other tissues including hemocytes and nervous tissues. In filarial nematodes, the bacteria are present in the female reproductive apparatus and lateral cords. In both nematodes and arthropods, Wolbachia is transmitted vertically (Brenner, Krieg, & Staley, 2005; Li, Floate, Fields, & Pang, 2014). Wolbachia was originally observed in the gonads of mosquito. Later studies indicated Wolbachia to be present in at least 20% of the sampled insect species. The bacterium has also been observed in samples of other classes of arthropods and nematodes.
Studies with microinjection in different host cells have demonstrated that Wolbachia strains responsible for infections in arthropods can tolerate the cellular environment of various hosts (Brenner, Krieg, & Staley, 2005). Wolbachia does not really cause obvious damage to its host cells. However, the bacteria present in arthropods are obviously pathogenic to male embryos (Brenner, Krieg, & Staley, 2005; Taylor, Bandi, & Hoerauf, 2005). In arthropods, Wolbachia infection is linked to alteration in host reproduction, which includes induction of parthenogenesis, killing of male embryos, cytoplasmic incompatibility (CI) and feminization of genetic males. It is worth noting that a bacterium is transmitted to the offspring through females since males are usually not integral in transmission (Brenner, Krieg, & Staley, 2005; Chirgwin, Coleman, Porthouse, Nowling, Punkosdy, & Klei, 2003). Wolbachia are cytoplasmically inherited group of bacteria, which result in more than a few reproductive alterations in insects including Cytoplasmic Incompatibility (CI). CI is an incompatibility between an egg and sperm, which results in loss of sperm motility or chromosomes following fertilization. Wolbachia is estimated to affect around 20% of all insect population, and present in isopods, arachnids and nematodes. Therefore, Wolbachia-induced IC is a critical factor that promotes rapid speciation in invertebrates.
According to Hoerauf et al. (1999) filarial nematode infection affects over 150 million people across the globe. In addition, there is a mutual interaction between Wolbachia and filarial nematode (Hoerauf et al., 1999). Therefore, investigation of such relationships is warranted for a prospective chemotherapeutic study. Even though elevated temperatures are also used to eliminate infections, the method is rarely applied. The duration of treatment required to remove Wolbachia from its host may range from few days to generations. Therefore, the success of the elimination method varies with the host species. Incidentally, most of the knowledge regarding treatment and side effect of eliminating Wolbachia is derived from experimental studies on few genera such as Diptera and Hymenoptera (Li et al., 2014). Numerous evidence outlines some valid apprehensions of altered immune response and development of resistance towards Wolbachia infections (Lammie, 2006; Li et al., 2014; Townson et al., 2000). This perspective demands the development of new antifilarial antibiotics with clear-cut underlying principle (Hoeurauf, 2006).
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Side Effects of Post-Antibiotic Use to Eliminate Wolbachia
There are different perspectives of evidence implicating Wolbachia in the side effects of anti-filarial therapy and the parthenogenesis of filariasis. Some of the acknowledged side effects of using antibiotics to remove Wolbachia from worms include sterility/ infertility/oogenesis inhibition, Death of Worms, loss of motility and sexual mosaics. Antibiotics such as Azithromycin, Doxycycline, Chloramphenicol, Rifampicin and Tetracycline are documented to be active against Wolbachia resulting in infertility, retardation and reduced viability of the parasite.
Sterility/ Infertility/Oogenesis Inhibition
There is the likelihood that the use of antibiotic to eliminate Wolbachia may be worse than the infection. The elimination of Wolbachia infections using antibiotics inhibits oogenesis (Puttaraju & Prakash, 2009; Pike & Kingcombe, 2009). Pike and Kingcombe (2009) pointed out that the elimination of Wolbachia from the collembolan Folsoma candida led to female sterility. Antibiotic curing leads to sterility and the elimination of Wolbachia endosymbionts (Pike & Kingcombe, 2009; Taylor, Bandi, & Hoerauf, 2005). In the same context, Dedeine et al. (2001) pointed out that female Nees, Asobara tabida cured of Wolbachia infections could not develop eggs (Li et al., 2014). Therefore, in both cases, it was impossible to maintain a sustainable colony of cured worms. Dedeine et al. (2001) notes that eliminating symbiotic Wolbachia bacteria from its hosts inhibits oogenesis, particularly in parasitic wasp. This is line with previous findings that Wolbachia causes a range of effects on reproduction and physiology. An investigation on the effect of Wolbachia infection in the parasitic wasp proved that the removal of Wolbachia through antibiotic treatment incapacitated aposymbiotic female wasps to produce mature oocytes. Consequently, the wasps could not reproduce. The investigation concluded that Wolbachia is necessary for oogenesis in the parasitic wasp, A. tibida (Dedeine et al., 2001).
Loss of Motility
From various studies, the use of Doxycycline and Tetracycline indicates significant loss of microfilarial (Mf) motility compared to other methods or controls for eliminating Wolbachia in worms (Chirgwin et al., 2003; Hoeurauf, 2006). Tetracycline is common, because it records a complete loss of Mf motility at minimum records. In the same context, Ciprofloxacin failed to record similar level of efficacy. Tetracycline is popular for its role against Wolbachia given that it is effective in controlling Mf release by the adult parasites influencing the reproduction process. Certain antibiotics including tetracycline and doxycycline were recently noted to be effective against Wolbachia coexisting symbiotically with filarial parasites (Townson et al., 2000). Wolbachia contributes to the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) formazan formation, which is used as a metric of filarial worm viability, in turn, suggesting that Wolbachia has a direct contribution to the metabolic activity of nematodes. The reduction of MTT to MTT formazan is an approved metric to determine the effects of antibiotics on worm viability and motility. In line with various studies, Wolbachia makes a significant contribution to the metabolic activity within hosts’ cells (Townson et al., 2000). Therefore, the inducement of antibiotics reduces the metabolic activity. Infection with Wolbachia contributes to extra metabolic activity in the cells. The results presented by several studies justify that O. gutturosa males are suitable model for human onchocerciasis. The gradual loss in motility is consistent with processes against the endosymbionts, which contrasts the rapid and direct effects of worm viability.
Sexual Mosaics
The other side effect of using antibiotic is sexual mosaic. In this case, all-male offspring are produced after the curing Wolbachia-infected females at adult stage. All the alterations caused by Wolbachia in the reproductive apparatus of the host have the overall effect of elevating the transmission rate of the bacteria. For example, feminization and parthenogenesis cause a Wolbachia-infected female host to generate more female offspring, which amplifies the transmission of the bacterium. In Cytoplasmic Incompatibility, embryonic death is noted after mating between infected males and females that are either infected or uninfected with incompatible strain of the bacteria (Brenner, Krieg, & Staley, 2005; Chirgwin et al., 2003). In other words, males that are infected by the bacterium do not transmit it, however, they sterilize females that are uninfected or those that carry dissimilar compatibility type of Wolbachia. The reduction in fitness of the uninfected females translates to an increase in the fitness of the infected females. Consequentially, the spread of Cytoplasmic Incompatibility Wolbachia is favored in the host population. Kageyama, Ohno, Hoshizaki, and Ishikawa (2003) proved that sexual mosaics are induced by the treatment of Wolbachia infected Ostrina scapulalis using tetracycline antibiotic. The female bean borer generates all-female broods or near all-female offspring. Treatment using tetracycline antibiotic during its larval stages led to the generation of all-male broods in the generation that followed (Kageyama et al., 2003). The sexual mosaics generated had wings composed of distinctive male and female sectors. In this end, the findings are consistent with the concept that Wolbachia has a feminizing effect; hence, treatment of the Wolbachia infection in O. scapulalis males generated sexually mosaic offspring.
Death of Worms
Antibiotics inhibit Wolbachia-dependent processes, with a resultant deterioration of nematode health. For example, the action mode of tetracycline is inhibiting protein synthesis. This indicates that the antibiotic treatment of Wolbachia infections is lethal to adult filariae. Wolbachia has a symbiotic relationship with their nematode hosts. Studies have shown that antibiotics such as tetracycline and doxycycline can eliminate the bacteria, which results in growth retardation and reduced viability (Chirgwin et al., 2003; Townson et al., 2000). On the other hand, uninfected nematodes are unaffected by exposure to antibiotics. Recent field trials of oxytetracycline antibiotic against onchocerciasis in cattle and of doxycycline in human onchocerciasis (River Blindness) have demonstrated the validity of this rationale. In all the tests, antibiotic treatment resulted in a significant reduction in microfilaraemia and a protracted inhibition of embryogenesis. River blindness is an incapacitating disease caused by filarial nematode Onchocerca volvulus. Langworthy et al. (2000) proved that the elimination of Wolbachia in nematode Onchocerca ochengi precedes worm death. The results of this report suggest that antibiotic tetracycline is microfilaricidal against Onchocerca ochengi since all the adult worms in the controlled trial were killed (Langworthy et al., 2000). Previous studies have indicated that worm survival is dependent of Wolbachia. Chirgwin et al. (2003) notes that elimination of Wolbachia from Brugia pahangi using antibitics is closely linked to fecundity and worm death. Wolbachia permits long-term reproduction and survival of some Onchocerca spp. including Onchocerca volvulus in humans.
With the realization that most filarial nematodes, especially those that are responsible for human filarial diseases are infected with Wolbachia, alternative strategies should be used to control and treat these parasites using antibiotics.
Discussion
The information in this paper will have implication on the approaches relating to testing and treatment of Wolbachia infections. Living and dead worms are disastrous. Living worms damage lungs, pulmonary arterial walls and the heart if left untreated. Dead or dying worms block blood flow, lodge in the arteries and cause platelets to cluster leading to complications like thromboembolism. The chances of respiratory or cardiovascular response to antibiotic treatment are associated to the worm burden. Therefore, a multimodal approach to treating worms is recommended (Li et al., 2014). The goal is to eliminate all the phases of worms and mitigate the cardio respiratory side effects. The stages of worms include microfilariae, larval, juveniles and adult worms (Brenner, Krieg, & Staley, 2005). The first move after diagnosis is to stabilize and animal with significant clinical signs and then pretreated with preventive antibiotic. Pretreatment kills the circulating endosymbiotic Wolbachia or microfilariae preventing further infection that would expand the worm burden. It is worth noting that continuous treatment prior to adulticide therapy to kill adult worms. Further, antibiotics help to kill the bacterium and endosymbiont inhabiting filarial nematodes such as Dirofilaria immitis that cause feline and canine heartworm (Bandi, McCall, Genchi, Corona, Venco, & Sacchi, 1999). According to Bandi et al. (1999), Wolbachia and D. immitis have a symbiotic relationship; they both depend on each other for survival. Wolbachia is found in all phases of D. immitis. Furthermore, they contribute to the pathogenesis of heartworm disease. Therefore, by eliminating Wolbachia, the worm biomass is decreased as well as the inflammatory response to the death of those worms. The key step in eliminating Wolbachia from worms using antibiotics is to understand the host-parasite relationship. Researchers have combed literature for using antibiotics to treat worms or canine rickettsial infections because Wolbachia is a rickettsial organism (Brenner, Krieg, & Staley, 2005; Gilbert et al., 2005).
To control human onchocerciasis, it is vital to develop an antibiotic (microfilaricide) lethal to adult Onchocercavolvulus. Gilbert et al. (2005) investigated the effects of the antibiotic oxytetracycline on the endosymbionts Wolbachia and the viability of adult worms and found that prolonged treatments eliminated over 80% of adult female worms and affected a sustained depletion of Wolbachia organisms (Gilbert et al., 2005). These results demonstrated the microfilaricidal potential of tetracycline against Wolbachia infection. In addition, it suggests that intermittent, protracted administration of antibiotics is more effective than continuous short-term treatment.
An evaluation of the available evidence on the possible side effects of using antibiotics to eliminate Wolbachia suggests that antibiotics cause post-antibiotic sterility. Contrary to prior perception, endosymbiont-catalyzed parthenogenesis may not be restricted to haplodiploids functionally (Pike & Kingcombe, 2009). Wolbachia serves as the main agent of this reproductive facilitation. This review explored numerous studies that report on treatment methods and outcomes for Wolbachia. The application of tetracycline antibiotic in the diet is the most popular method and is typically successful (Hoerauf et al., 1999). When tetracycline is not successful, Rifampicin is used. Despite the fact that filarial worms have a diffident importance in veterinary medicine, the discovery of Wolbachia continues to contribute to innovate research and advances in biological vector analyses. Much remains to be studied, especially future studies on the therapeutic advantages of antibiotic treatments designed to eliminate Wolbachia load in adult worms.
Conclusion
After the observation that filarial parasites host endosymbiotic bacterium, Wolbachia, it has been discovered that tetracycline and other anti-Wolbachia antibiotics interfered with worm, fertility, motility and sexual mosaic. In the agreement with previous studies, Rifampicin, doxycycline and tetracycline are some of the most effective antibiotics. The antibiotic exposure has a sterilizing effect and killing of worms. In addition, the exposure results in sexual mosaics and loss of motility. These discoveries triggered interest in the contribution of Wolbachia bacterium to the pathogenesis of filarial diseases, as well as the interest in the prospective application and side effects of antibiotics in the elimination of Wolbachia. A shorter course of chemotherapy reduces the microfilarial level, and the incidences of the inflammatory response are encouraging and justify the concept that Wolbachia are an attractive target for antibiotic interventions. However, the duration of treatment is still a hurdle, particularly from a public health perspective. Longer courses of treatment with any antibiotic also raise the risk of adverse effects. Therefore, the potential impact of mass treatment with antibiotics on the materialization of antibiotic resistance by non-targeted endosymbionts must also be considered. Further research is needed to develop additional antibiotic interventions. Either killing or sterilization of adult worms would accelerate the sensation of the elimination process and could make the elimination of onchocerciasis feasible in the tropics. In spite of the fact that developing antibiotics that kill adult worms directly seems to be an optimum research approach, there is a considerable advantage of targeting Wolbachia. From a biological perspective, the sterilization of adult worms is as successful as killing them. Given that the preferential locations of adult worms, antibiotics with macrofilaricidal activity are linked to reactions with, may be painful and reduce MDA (Mass Drug Administration). Additional research on tetracycline and related antibiotics is also warranted. This is a subject to the notion that the impact of antibiotics on filarial parasites may surpass its effects on Wolbachia.
