The Wolbachia endosymbiont as an anti-filarial nematode target

Abstract

Human disease caused by parasitic filarial nematodes is a major cause of global morbidity. The parasites are transmitted by arthropod intermediate hosts and are responsible for lymphatic filariasis (elephantiasis) or onchocerciasis (river blindness). Within these filarial parasites are intracellular alpha-proteobacteria, Wolbachia, that were first observed almost 30 years ago. The obligate endosymbiont has been recognized as a target for anti-filarial nematode chemotherapy as evidenced by the loss of worm fertility and viability upon antibiotic treatment in an extensive series of human trials. While current treatments with doxycycline and rifampicin are not practical for widespread use due to the length of required treatments and contraindications, anti-Wolbachia targeting nevertheless appears a promising alternative for filariasis control in situations where current programmatic strategies fail or are unable to be delivered and it provides a superior efficacy for individual therapy. The mechanisms that underlie the symbiotic relationship between Wolbachia and its nematode hosts remain elusive. Comparative genomics, bioinfomatic and experimental analyses have identified a number of potential interactions, which may be drug targets. One candidate is de novo heme biosynthesis, due to its absence in the genome sequence of the host nematode, Brugia malayi, but presence in Wolbachia and its potential roles in worm biology. We describe this and several additional candidate targets, as well as our approaches for understanding the nature of the host-symbiont relationship.

A feedback loop betweenWolbachiaand theDrosophila gurkenmRNP complex influencesWolbachiatiter

“…It is known that Wolbachia endosymbionts of Onchocerca volvulus, Wuchereria bancrofti and Brugia malayi contribute significantly to African river blindness and lymphatic filariasis (Saint Andre et al, 2002;Debrah et al, 2006;Debrah et al, 2007;Taylor et al, 2008;Debrah et al, 2009;Turner et al, 2009). Because elimination of Wolbachia from these nematodes disrupts both the filarial host and manifestations of disease (Johnston and Taylor, 2007;Slatko et al, 2010), any insight into Wolbachia titer control is potentially useful. The recently sequenced Brugia genome does not appear to encode a grk gene, but it has possible homologs for hrb27C and sqd, as well as for the grk mRNA-binding proteins Bruno/Aret, Imp and Orb (Chang et al, 1999;Filardo and Ephrussi, 2003;Geng and Macdonald, 2006;Ghedin et al, 2007).…”

Onchocerciasis: the Role of Wolbachia Bacterial Endosymbionts in Parasite Biology, Disease Pathogenesis, and Treatment

“…Target discovery approaches have also been advanced to provide a core list of essential genes and enzyme targets in pathways validated as important to the Wolbachianematode symbiosis (39,41,61,87).…”

“…Our understanding of the biological basis of the symbiotic relationship is limited and is based on comparative genomics of Wolbachia and host nematodes. This has suggested that various biochemical pathways which are intact in Wolbachia but absent or incomplete in the nematode, including heme, nucleotide, and enzyme cofactor biosynthesis, are candidates for Wolbachia's contribution to nematode biology (61).…”

Autophagy regulates Wolbachia populations across diverse symbiotic associations

“…Although the molecular basis of this mutualistic relationship remains unknown, a comparison of host and bacterial genomes suggests that intact biosynthetic pathways for haem, nucleotides, riboflavin, and FAD may be among the contributions of the bacteria to the biology of the nematode host (6)(7)(8). The biological processes most sensitive to Wolbachia loss include larval growth and development and embryogenesis in adult females.…”