Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Cathy Savage-Dunn

Committee Members

John Dennehy

Alicia Melendez

Shubha Govind

Niels Ringstad

Subject Categories

Biology | Immunity

Keywords

C. elegans, innate immunity, cell signaling

Abstract

When exposed to infection, the nematode C. elegans mounts an innate immune response through secretion of antimicrobial peptides (AMPs). Different signaling pathways in the worm regulate release of these AMPs. One highly conserved pathway is the C. elegans BMP like pathway – regulated by the ligand DBL-1. The DBL-1 pathway is noted for its significant role in development but has also been shown to regulate many post-developmental processes within the worm, including the immune response. We are interested in determining how DBL-1 signaling can mediate a response specific to immunity, separate from its other functions in the worm. Through survival analysis we have shown that when exposed to pathogenic bacteria, expression of the DBL-1 effector SMA-3 in either the hypodermis or pharynx improves survival rate compared to sma-3 mutants. These results suggest crosstalk between the pharynx and the intestinal site of infection. Using qRT-PCR we have found two immune-related genes with expression patterns that indicate regulation by DBL-1 signaling through SMA-3. We have demonstrated that sma-3 expression in either the hypodermis or pharynx is sufficient to induce expression of these two AMPs in infection conditions. These results suggest that non cell- autonomous signaling of the DBL-1 pathway to regulate gene expression plays a role in the response to infection. We have also looked at the role that all five TGF- β ligands – DBL-1, TIG- 2, T IG-3, UNC-129, DAF-7 – play in the C. elegans immune response and show that mutations in any of these ligands have an effect on survival against bacterial infection. Through the use of double mutant analyses, we have shown that multiple TGF- β ligands demonstrate cooperative interaction in the immune response. Finally, we have shown that multiple canonical signaling components of the DBL-1 pathway are involved in the response to bacterial infection, whereas the DAF-7 R-Smad DAF-14 has no effect on survival. Taken together, our work shows that when faced with bacterial infection C. elegans mounts an immune response that uses complex signaling from the five TGF- β ligands and that through DBL-1, regulation of AMP expression is mediated by non cell-autonomous signaling.

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