Authors:

Amelia Kotamarti

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About Paper:

Sounding the cellular alarm: Uncovering mechanisms of immune receptor activation Co-Author(s): Lauren Chisholm, Mike Harms Annually, 1. 7 million adults in the US develop sepsis, a life-threatening condition where the immune system becomes overactive in response to a bacterial infection. TLR4, an immune receptor, plays a key role in this overactivation. TLR4 is activated by LPS, an oily molecule made by bacteria, through a well- described mechanism. First, LPS is carried by a helper protein, CD14, to the active site of TLR4, initiating an inflammatory pathway. Next, if CD14 is tethered to the cell membrane, a second inflammatory pathway is initiated. TLR4 can also respond to other danger signals, such as S100A9, an inflammatory cytokine. S100A9 has been implicated in multiple illnesses, including Alzheimer's Disease, but attempts to use it as a drug target have failed due to a lack of knowledge about its mechanism of action. Using an assay in mammalian cells, we demonstrate that if CD14 is not tethered to the cell membrane, S100A9 cannot activate inflammation, while LPS can. These results suggest that S100A9 may only be able to activate the second inflammatory pathway, not the first. Current experimental methods measure a general inflammatory output. To ameliorate this lack of specificity, I am developing a novel assay that will differentially measure activation levels of the two pathways. Understanding how much S100A9 activates each of these two pathways will help uncover S100A9's mechanism of action, making it an easier drug target. 199 UNIVERSITY OF OREGON • 2025 UNDERGRADUATE RESEARCH SYMPOSIUM TABLE OF CONTENTS

Source:

University of Oregon / 2025

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Co-authors:

Amelia Kotamarti