Degree Type

Dissertation

Date of Award

2016

Degree Name

Doctor of Philosophy

Department

Biomedical Sciences

Major

Molecular, Cellular and Developmental Biology

First Advisor

Michael J. Kimber

Second Advisor

Lyric C. Bartholomay

Abstract

Lymphatic Filariasis (LF) is a Neglected Tropical Disease, caused by mosquito-borne filarial nematodes including Brugia malayi, which infects over 120 million people. Mass drug administration is used for LF control but limited efficacy of the drugs combined with the threat of resistance drives the need for novel control strategies. Chemosensation is an essential behavior used by nematodes, including parasitic species, has roles in development, avoidance of noxious stimuli and finding food/mates/hosts, making genes involved in this system attractive targets for parasite control. Little, however, is known about the chemosensory system in parasitic nematodes. Here we address this knowledge gap and describe the structural, behavioral and genetic basis for chemosensation in filarial nematodes. Sensory structures and their innervation are identified in larval and adult stages of B. malayi using scanning electron and fluorescent microscopy. In addition, behavioral responses of B. malayi L3 stage parasites to host-derived stimuli were profiled and specific tactic behaviors that may be important in host-seeking and host-invasion identified. To further characterize the genetic basis for chemosensation in B. malayi, we surveyed heterotrimeric G-proteins (known mediators of nematode chemosensation) on a pan-phylum level using bioinformatic and phylogenetic approaches. This analysis revealed highly conserved and novel patterns of gene expression that may be exploited for novel LF control strategies. While the characterization of chemosensation in B. malayi has revealed one mechanism by which the nematode interacts with its environment, interactions between the nematode and host (both mosquito and human) are far more complex. Here we also present results, which demonstrate for the first time that parasitic nematodes of humans use exosomes, a specific type of extracellular vesicle, to deliver bioactive molecules capable of manipulating the host-parasite interface. We show L3 stage B. malayi release extracellular vesicles of the size and shape of exosomes in prodigious quantities. The cargo of these vesicles includes exosomal markers and putative effector proteins as well as an abundant microRNA complement suggesting a role in host manipulation. The parasite vesicles are rapidly internalized by host macrophages where they stimulate a classically activated phenotype. These results suggest a novel mechanism by which human parasitic nematodes may actively direct the host responses to infection and could seed new therapeutic strategies for LF control.

Copyright Owner

Lisa Marie Fraser

Language

en

File Format

application/pdf

File Size

197 pages

Share

COinS