Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Genetics, Development and Cell Biology

Major

Genetics and Genomics

First Advisor

Michael Kimber

Abstract

Lymphatic filariasis (LF) is a neglected tropical disease that affects over 120 million people worldwide and is caused by three filarial nematodes including Brugia malayi. Despite mass drug administration (MDA) to populations at risk for over 17 years, LF still remains a global health concern. Parasitism depends on specific interactions between the parasite and host. Our efforts of understanding these intricate interactions revealed a novel mechanism through which Brugia actively delivers small regulatory RNA and proteins to the host tissues via exosomes-like vesicles (ELV). Proteomics reveal stage and gender specific cargo, including proteins with potential immunomodulatory capacity. This suggests not only stage specific modulation of the host but also potential sexual dimorphism, and supports the hypothesis that these vesicles are released by the parasite to cater to its survival within the host. We have shown that these ELVs are functional and elicit a stage specific response in host macrophages, further supporting the above hypothesis. Further exploration of the possibility of exploiting these ELVs in disease control efforts revealed that exosomal release in these parasites is inhibited by current anthelmintics used to treat LF including ivermectin (IVM). Previous studies suggest a host component in parasite clearance by IVM and the fact that ELV release is inhibited by IVM not only supports this hypothesis but also provides evidence for how such a mechanism might take place. If our hypothesis that ELVs are released by these parasites to immunomodulate the host to aid in survival within the host is true, then inhibition of these vesicle by IVM leaves the parasites vulnerable to host defense mechanisms, thereby allowing effective parasite clearance. The use of ELV release inhibition as a platform for screening novel drugs resulted in the identification of a panel of L-type calcium channel inhibitors that block exosomal release in these parasites more potently than IVM. Current diagnostic methods for LF are suboptimal and here we demonstrate proof of principle of using miRNA as biomarkers for more accurate diagnosis. Collectively our results reveal a novel mechanism in Brugia and demonstrate the potential of exploiting it in a wide spectrum of control efforts.

Copyright Owner

Hiruni Harischandra

Language

en

File Format

application/pdf

File Size

165 pages

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