From Host to Pathogen: Caenorhabditis elegans as a model host system to study Basic Innate Immunity and Antimicrobial Drug Discovery

Escobar, Iliana E.

Full Metadata

Overview

Year:: 2021
Contributor:: Escobar, Iliana E (creator); Belenky, Peter (Reader); Sanders, Jennifer (Reader); Lefort, Craig (Reader); Mylonakis, Eleftherios (Advisor); Ausubel, Frederick (Reader); Brown University. Biology and Medicine: Pathobiology (sponsor)
Genre:: theses
Subject:: Immune response; Caenorhabditis elegans; Antibiotics; antimicrobial resistance; High Throughput Screening
Extent:: Xi, 173 p.

Files

Description

Abstract:: Host-microbe interactions heavily influence both fitness and disease. Traditionally, research on host-microbe interactions focused on the concept that microbes only contribute to pathogenesis. However, recent studies have begun to elucidate the positive influence of microorganisms on human immunity and development. These findings broaden the scope of host-microbe interactions and highlight the need for novel and multidisciplinary approaches for research. In this thesis, I focus on the study of basic innate immunity and antimicrobial discovery using Caenorhabditis elegans as a whole-animal infection model. I first examine basic mechanisms underlying C. elegans innate immunity by reporting the evolutionarily conserved function of sphingolipid sphingosine-1-phosphate (S1P) and a non-canonical role for S1P transporters in the C. elegans immune response. We then show how S1P activity is dependent on the known C. elegans immunity pathway p38 MAPK and transcription factor hlh-30. Next, I present the utility of the C. elegans infection model for antimicrobial drug discovery via high-throughput screening. I examine two hit compounds from this screen; kinase inhibitors IMD0354 and Bay 11-7085. I show that IMD0354 is a potent antimicrobial against Gram-positive bacteria with a low minimum inhibitory concentration (MIC) of 0.06 µg/ml. Moreover, IMD0354 can inhibit S. aureus single-cell attachment and prevent biofilm formation at or above MIC concentrations. I then found that high concentrations of IMD0354 can affect cell permeability. Finally, I examine how Bay 11-7085 exhibits anti-infective activity to both S. aureus and Candida spp. at an MIC of 0.5-4 µg/ml. Importantly, I show that Bay 11-7085 inhibits three stages of biofilm maturation, both in monoculture and in a polymicrobial culture of S. aureus and C. albicans. Lastly, I detail how Bay 11-7085 possesses a low probability of antibiotic resistance and can effectively save worms from lethal infections by S. aureus and C. albicans. Through these works, I conclude that the C. elegans- infection model is dynamic enough to study both ends of host-microbe interactions. We find this platform a promising bridge between basic and translational research capable of advancing antimicrobial drug discovery.
Notes:: Thesis (Ph. D.)--Brown University, 2021

Content

Citation

Escobar, Iliana E., "From Host to Pathogen: Caenorhabditis elegans as a model host system to study Basic Innate Immunity and Antimicrobial Drug Discovery" (2021). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:wxkfgsnd/

Relations

Collection:

Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
...