Brugia: molecular mechanisms of filarial endosymbiosis
Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are two debilitating and far-reaching neglected tropical diseases. There is a need for drugs that target the adult stages of this family of parasitic worms. The overriding goal of this project is to understand how filarial nematodes such as Brugia malayi—a causative agent of lymphatic filariasis—are able to survive within their infected host for extended periods of time, avoiding, evading, and actively modulating their host’s immune response.
We address key questions on effectors at the host-parasite interface, and on the reciprocal cues required for the co-dependency of B. malayi with its essential intracellular bacterial endosymbiont, Wolbachia. We use a systems biology approach that includes transcriptomics, proteomics, metabolomics, glycomics, and in silico metabolic reconstructions to identify networks of co-expression necessary for maintaining endosymbiosis between filarial parasites and their Wolbachia.
- To identify how networks of co-expression change over the lifecycle of the parasite
- To identify pathways essential at the host interface that could be targeted in the worm
- To explore parasite regulatory networks that control mechanisms of symbiosis
- To discover novel molecules with therapeutic potential beyond parasite control
Clustering of stages and Wolbachia DE genes.
Hierarchical clustering of Wolbachia DE genes and developmental stages, L4 through 120 days post infection (dpi) male (M) and female (F), based on gene expression in normalized FPKMs. Expression values were scaled prior to clustering using a Z score calculation, with red representing high expression and blue representing low expression. Biological replicates were combined prior to clustering.
The co-expression network for B. malayi and Wolbachia.
The network heatmap plot of network connectivity for B. malayi and Wolbachia calculated using weighted gene correlation network analysis (WGCNA). The black branches show the hierarchical clustering dendrograms, which were assigned to clusters using dynamic tree cutting to identify modules of co-expressed genes, shown as colored bars. High co-expression interconnectedness is indicated by increasingly saturated orange and red coloring. Modules correspond to groups of highly interconnected genes.