Detect and treat system for inflammation using synthetic receptors

The National Institute of Allergy and Infectious Diseases awarded the Regents of the University of Michigan $100,228 on February 13, 2027, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop engineered cell-based systems that detect and treat sepsis through synthetic receptors targeting alarmin proteins S100A8 and S100A9.

The project will explore two complementary cell engineering strategies: engineering cells to constitutively secrete therapeutics that modulate S100A8/A9 signaling as proof-of-concept for cell therapy in sepsis, and developing synthetic receptors that detect sepsis biomarkers and deliver diagnostic or therapeutic responses. The work targets S100A8/A9 because clinical studies show strong correlation between levels of these proteins and sepsis severity and activity, and because S100A9-deficient mice demonstrate reduced endotoxin-induced lethal shock and increased survival compared to wild-type mice. Improved early detection of sepsis biomarkers and shortened time to treatment could substantially improve outcomes in a disease that causes approximately 270,000 fatalities yearly in the United States.

Work is performed at the University of Michigan in Ann Arbor, Michigan, with a period of performance ending August 31, 2028. The funding is classified as a Project Grant, an assistance type supporting investigator-initiated research at academic institutions.

Abstract

Synthetic biology and genetic engineering are expanding the possibilities of cell therapy, offering new strategies to diagnose and treat complex diseases. Inflammatory disorders pose a significant global health burden and are expected to rise over the next 30 years. Leveraging engineered cell-based approaches for diagnosing and treating these conditions could profoundly impact patient outcomes. Among inflammatory disorders, sepsis is a major target for developing new treatments, with approximately 270,000 fatalities yearly in the united states alone. Sepsis is characterized by a dysregulated and often fatal immune response to infection, leading to tissue and organ damage. Current screening tools for early identification are not sufficiently sensitive, and the lack of standardized diagnostic criteria leads to diagnostic uncertainty and delays in treatment. A system that detects sepsis biomarkers and delivers a diagnostic reporter or therapeutic upon detection would shorten the time to treatment and improve patient outcomes. Alarmin proteins S100A8 and S100A9 play key roles in the pathogenesis of sepsis, making them promising therapeutic targets and biomarkers for cell-based interventions. These proteins are secreted by neutrophils and monocytes, contributing to pro-inflammatory processes through receptors such as toll-like receptor 4 (TLR4). Clinical studies demonstrate that the levels of S100A8/A9 strongly correlate with the severity and activity of sepsis. Additionally, S100A9-deficient mice experience reduced endotoxin-induced lethal shock and increased survival relative to wild-type mice. This project will explore two complementary cell engineering strategies targeting S100A8/A9 in sepsis: (1) engineer cells to constitutively secrete therapeutics that modulate S100A8/A9 signaling, providing proof-of-concept for cell therapy in sepsis; and (2) develop synthetic receptors using modular extracellular sensor architecture (mesa) to enable biomarker-responsive detection and intervention targeting soluble S100A8/A9. By implementing both constitutive and S100A8/A9-inducible cell-based secretion strategies, i hypothesize that these approaches will yield effective and adaptable diagnostic and therapeutic platforms for sepsis. Aim 1 will develop engineered cells to constitutively secrete modulators of S100A8/A9 signaling, representing a foundational proof-of-concept for cell therapy in sepsis. Aim 2 will develop a mesa receptor that, when activated by S100A8/A9, triggers therapeutic release. Preliminary data show successful identification of a nanobody that modulates S100A8/A9-TLR4 interactions and successful engineering of a S100A8/A9-responsive mesa system. This fellowship will provide the necessary tools to help me achieve my goal of becoming a physician-scientist dedicated to discovering innovative treatments for poorly treated conditions using synthetic biology.