Host-pathogen interactions in filarial worm infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Neglected tropical diseases caused by parasitic nematodes such as the filarial parasite Brugia malayia causative agent of lymphatic filariasis, also known as elephantiasisremain a leading cause of morbidity and a significant health burden in the developing world. The continued lack of effective vaccines and the limited outcomes of mass drug administration efforts highlight the need for non-traditional therapeutic approaches. Such approaches require a deeper understanding of the underlying biology of parasitism and a clear definition of the host-parasite interface. This project is divided into two related components: one aspect focuses on the interaction of Brugia malayi worms with their mammalian host, and the other on the interaction of the worm with its Wolbachia bacterial endosymbiont. We have integrated transcriptomic, proteomic, and glycomic data to define the stage and sex-specific secretomesthe primary host-parasite interfaceof B. malayi and characterized protein glycosylation. The diverse role of glycosylation has been reported in the literature yet remains understudied for any human filarial nematode. Our work aims at bridging this gap as we report sex-specific glycosylation of proteins secreted by male and female worms, including previously characterized immunomodulators. Our findings highlight that control of these infections could be approached by differential targeting of male and female worms. In our current experiments we investigate how male and female worms interact with the host lymphatic system and the immune system. Using lymphatic epithelial cells, PBMCs, and live worms, we are testing how they are impacted by recombinantly expressed putative lipid-binding proteins that are differentially glycosylated between male and female worms. Through metabolomics experiments we have identified novel short chain fatty acids that are exclusively secreted by male worms. We are evaluating the effects of these metabolites, that we have synthesized, to impact the transcriptional program of lymphatic epithelial cells. This project also evaluates how Wolbachia impact the regulation of host worm genes, how they obtain essential metabolites for their survival, and how they evade the hosts intracellular immune defenses. Wolbachia are common intracellular bacteria found in arthropods and filarial nematodes. The association between filarial worms and their mutualistic and obligatory endosymbionts is different from that of Wolbachia with insects: in worms they appear to provide crucial elements for fitness and survival, whereas the insects are mostly viable without Wolbachia. We are evaluating how Wolbachia change the transcriptional profile of the host cells they infect. We have identified miRNAs that are differentially regulated in response to Wolbachia disruption in B. malayi worms, and we are testing miRNAs identified as differentially expressed in mosquito cell lines with or without Wolbachia. We aim to characterize host genes that are regulated by Wolbachia via miRNA manipulation. We are also looking at the induction of cellular autophagy which was shown to drastically decrease the number of bacteria in worms, and to block embryogenesis and the release of microfilariae (Mf) by treated female worms. We have identified chemical compounds that induce autophagy in nematodes, and are testing their ability to eliminate Wolbachia in adult worms. The results from our research could help direct future investigations into a defined set of B. malayi genes that are important for maintaining the Wolbachia-filarial worm mutualistic co-dependencies, and aid in the search for novel macrofilaricidal drugs that affect symbiosis. Probing the mechanisms of interaction of the filarial worm Brugia malayi with its bacterial symbiont, Wolbachia, and of the worm with its host will give insight into the unique biology of this family of important pathogens. This could better inform novel therapeutic strategies.