Date of Award

Winter 12-12-2025

Degree Type

Thesis

Degree Name

Master of Science in Biology

Department

Biology

First Advisor

Sangman Kim

Second Advisor

Mary Jane Niles

Third Advisor

Christina Tzagarakis-Foster

Abstract

Toll-like receptors (TLRs) are a subclass of pattern recognition receptors within the

innate immune system that detect pathogen-associated and danger-associated molecular patterns,

thereby initiating host defense responses. The human TLR family comprises ten receptors (TLR1

– TLR10), each recognizing structurally conserved microbial motifs such as bacterial

lipoproteins and viral nucleic acids. The ligand specificities, adaptor protein recruitment, and

downstream signaling cascades have been well-characterized for TLR1 – TLR9, which

predominantly engage MyD88- or TRIF-dependent pathways to activate pro-inflammatory

transcription factors including NF-κB. In contrast, the ligand specificity and intracellular

signaling mechanisms of TLR10 have yet to be fully elucidated. Emerging evidence suggests

TLR10 may serve as a negative regulator of inflammation, in stark contrast to the canonical pro-

inflammatory roles of the other TLRs. A nonsynonymous single nucleotide polymorphism,

rs4129009 (Ile775Val), within TLR10 has been associated with several inflammatory and

immune-mediated diseases, including rheumatoid arthritis, bladder and prostate carcinomas, and

tuberculosis. These associations suggest that proper TLR10 function is critical for maintaining

immune homeostasis and restraining pathological inflammation. This study systematically

investigates the impact of rs4129009 on TLR10 plasma membrane localization,

heterodimerization potential with other TLRs, and downstream signal transduction. Defining the

molecular mechanisms by which rs4129009 alters TLR10 function will advance our

understanding of its regulatory role in innate immunity and inform the potential therapeutic

targeting of TLR10 in inflammatory pathologies.

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