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  • Many filarial species harbor an endosymbiotic bacterium of t

    2020-07-08

    Many filarial species harbor an endosymbiotic bacterium of the genus Wolbachia. A recent investigation of Wolbachia distribution in 35 filarial species including 28 species and 7 genera and/or subgenera have shown that 37% of them harbor Wolbachia (Ferri et al., 2011). In filarial nematodes, Wolbachia appear to have evolved towards a mutualistic symbiosis. Genomic information for B. malayi and its endosymbiont Wolbachia have enabled us to better understand this co-dependency (Foster et al., 2005a, Ghedin et al., 2007, Slatko et al., 2010). As the endosymbiont has limited biosynthetic capabilities, it is highly plausible that the host supplements Wolbachia with amino acids required for growth (Foster et al., 2005a, Foster et al., 2005b). Conversely, Wolbachia appears to supply the filarial host with riboflavin, flavin GSK J1 dinucleotide, nucleotides and possibly also heme, although the recent genome study of Loa loa, which does not harbor Wolbachia indicates that this might be overly inferred (Desjardins et al., 2013). Notably, the endosymbiont appears to be essential for optimal filarial development in the definitive human host, including development of L3 to L4 and reproduction; as such, it has become a target for the development of novel chemotherapeutic drugs (Foster et al., 2005a, Slatko et al., 2010, Johnston et al., 2014, Taylor et al., 2014). Wolbachia appears to be less important for L1 to L3 development in the intermediate host (Arumugam et al., 2008). Treatment of humans with antibiotics was shown to have a strong anti-filarial effect, confirming the essential role Wolbachia plays in survival and reproduction of the worm. For example, antibiotic treatment of W. bancrofti or O. volvulus-infected patients with doxycycline resulted in a long-term embryostatic effect, sterility of adult female worms with a sustained reduction of microfilarial loads (Taylor et al., 2010, Hoerauf et al., 2011). Notably, this treatment resulted also in slow death for the adult worms, with the majority of the worms (70% for onchocerciasis and 90% for LF) dying 2years after treatment, with subsequent improvement in the pathological manifestations of both diseases (Debrah et al., 2006, Debrah et al., 2007, Debrah et al., 2011, Hoerauf et al., 2008, Specht et al., 2008, Specht et al., 2009). To better understand endosymbiosis at the molecular level and the dependency of B. malayi on its endosymbiont, we analyzed B. malayi gene expression patterns in response to depletion of Wolbachia by tetracycline treatment in vivo (Ghedin et al., 2009). This study highlighted B. malayi metabolic pathways—including proteolysis, translation, energy metabolism, and signal transduction—as being affected by Wolbachia depletion, thus indirectly implicating them in the endosymbiotic relationship (Ghedin et al., 2009). Some of the most up-regulated genes encoded proteins known to be involved in regulating degradation of intracellular proteins, including the cathepsin L-like cysteine proteases Bm-cpl-3 (Wormbase gene ID WBGene00233004) and Bm-cpl-6 (WBGene00233058). Bm-cpl-3 was up-regulated at day 7 post-treatment while Bm-cpl-6 was up-regulated at day 14 post-treatment. In comparison, Bm-cpl-4 (WBGene00227937) was down-regulated 7 and 14days after depletion of the endosymbiont with tetracycline (Ghedin et al., 2009). The regulation of the cathepsin L-like cysteine proteases by tetracycline treatment was of interest, as it identified a potential connection between the essential dependency of the filarial parasite on Wolbachia and the known functions of these proteins in the filarial host (Ghedin et al., 2009). Remarkably, the role of Wolbachia during filarial development, molting and embryogenesis is similar to the roles attributed to these proteases in filarial development (Lustigman et al., 1992, Lustigman et al., 1996, Lustigman et al., 2004, Tort et al., 1999, Guiliano et al., 2004, Ford et al., 2009). In B. malayi, two clade I subfamilies of the cathepsin L- like cysteine proteases (Bm-CPL) were identified (Guiliano et al., 2004): clade group Ia includes Bm-CPL-1, -4 and -5, and clade Ic includes Bm-CPL-2, -3, -6, -7 and -8. The cathepsin-L like proteases of group Ia have been studied extensively (Britton and Murray, 2004, Britton and Murray, 2006, Guiliano et al., 2004, Ford et al., 2009), and were shown by RNA interference (RNAi) to be essential for molting of O. volvulus larvae (Lustigman et al., 2004) and B. malayi larvae (Song et al., 2010), as well as for embryogenesis in B. malayi female worms (Lustigman et al., 2004, Ford et al., 2009). Electron microscopy analysis of adult female worms treated with double-strand RNA corresponding to Bm-cpl-5 indicated that the number of Wolbachia in the hypodermis of the adult worms as well as in microfilariae were much reduced in the RNAi treated worms, as compared to the untreated controls. In comparison, the number of Wolbachia in the oocytes and embryos was similar to those of normal worms (Ghedin et al., 2008). To further understand the possible role of the filarial cysteine proteases during symbiosis we focused in the present study on the group Ic cathepsin-L like proteases, since expression of Bm-cpl-3 and Bm-cpl-6 is modulated by Wolbachia depletion (Ghedin et al., 2009) and very little is known about these proteins.