The endosymbiont Wolbachia rebounds following antibiotic treatment

Abstract

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.

Computational Design and Preliminary Serological Analysis of a Novel Multi-Epitope Vaccine Candidate Against Onchocerciasis and Related Filarial Diseases

“…Though the initial target date to stop treatment in all foci in all six endemic countries in the Americas was 2012, onchocerciasis; however, remains prevalent in Venezuela and Brazil despite the fact that the Onchocerciasis Elimination Programme for the Americas (OEPA) implemented a biannual and tetra-annual distribution of ivermectin (IVM) in contrast to the annual treatments in Africa where the endemic foci are relatively larger and even inaccessible in some cases [ 15 , 16 ]. On the other hand, onchocerciasis elimination in Africa faces, amongst other challenges, the possible emergence of parasite resistance to ivermectin which is the only effective drug currently used for control [ 17 ], the contraindication of ivermectin in patients co-infected with high titres of Loa loa [ 18 ], the emergence of recrudescence [ 10 , 19 ], the absence of robust diagnostic tools [ 20 ], the lack of safe and efficacious vaccines [ 10 ], and the potential emergence of resistance to the antibiotic doxycycline which targets the Wolbachia endosymbiont of the parasite [ 21 ]. The situation in Africa may therefore be precarious considering that greater than 99% of the infected and over 96% of the 198 million people at risk live in Africa [ 22 ].…”

The Eagle effect in the Wolbachia-worm symbiosis

“…The mechanism of action is not yet known for the new quinazolines, CBR417 and CBR490, but these compounds resulted in findings similar to those of rifampicin in vivo . Animal studies have shown that these compounds decreased Wolbachia titers by 90–99% compared to vehicle controls [ 33 , 36 , 39 ], which suggests that worms recovered from treated animals may correspond to those worms that were exposed to low (1–10 µM) concentrations of antibiotics in the present in vitro study. Thus, worms recovered in vivo receive what may be the equivalent of low doses in vitro .…”

“…In an in vivo study by Gunderson et al [ 39 ], Wolbachia titers were initially reduced following rifampicin treatment but then returned to normal levels 8 months later. They reported that populations of Wolbachia found within clusters were not reduced by antibiotic treatment, but that Wolbachia in the areas surrounding the clusters were eliminated, suggesting that these clusters contained Wolbachia in a protected state.…”

“…Antibiotics such as rifampicin and minocycline, as well as novel anti- Wolbachia drugs, have also shown promise in pre-clinical models of lymphatic filariasis and onchocerciasis [ 19 , 32 – 37 ]. However, there is evidence in pre-clinical models that if insufficient anti- Wolbachia treatment is administered, Wolbachia can repopulate their host leading to recovery of filarial fecundity [ 35 , 38 , 39 ].…”

Transcriptomic Analysis Reveals the Sexually Divergent Host–Wolbachia Interaction Patterns in a Fig Wasp

“…To investigate the interactions between Wolbachia and insect hosts, Wolbachia is usually artificially eliminated from the Wolbachia -infected hosts through antibiotic treatment. However, antibiotic treatment may produce negative effects to the hosts which interfere with the final analyses, such as changing the composition of the gut microbes of the hosts, producing a strain-specific response to antibiotics and Wolbachia rebounds appearing [ 11 , 12 ]. If an insect model with a native distinction of Wolbachia infection (infected or noninfected) between different individuals within the same species, or between two closely related sibling species can be used, we can accurately infer the influences of Wolbachia on the hosts.…”