CAREER: Survival Strategies: Using Contextual Cues for Accurate Cell Decision-Making in Changing Environments

Organisms often face life-and-death decisions under time pressure, such as adapting to sudden environmental changes or evading predators. Understanding how organisms make accurate, time-sensitive decisions with incomplete information is critical to determine how they process and respond to environmental signals. This project focuses on understanding how the bacterial pathogen Salmonella Typhimurium makes time-sensitive decisions when engulfed by immune cells.

Using quantitative approaches to track decision-making in single bacteria in real-time, this research investigates how Salmonella balances speed and accuracy to survive the hostile environment of an immune cell. Understanding how bacteria make life-and-death decisions in this environment could lay the groundwork to disrupt bacterial decision-making as a means to treat disease.

This project will generate fundamental new knowledge about cellular decision-making, with potential applications in synthetic biology, such as designing bacteria for sustainable agriculture, pollution cleanup, and disease diagnosis. The interdisciplinary educational component introduces high school students to cutting-edge artificial intelligence (AI) techniques through a hands-on curriculum integrating biology, coding, and imaging.

When engulfed by a macrophage, Salmonella must rapidly adapt to the phagosome environment and activate virulence genes to survive. Activation of virulence genes is time-sensitive, as the host is actively attempting to neutralize the bacteria. However, phagosomal stimuli appear gradually and heterogeneously, making it challenging for the bacteria to rapidly classify this new environment.

This project investigates how Salmonella use contextual cues for rapid and accurate decision-making in the intracellular environment. By combining microfluidics and live-cell imaging, this project tracks virulence responses at the single-cell level to determine how contextual cues impact the accuracy of the response. This research will position us to predict and perturb bacterial decision-making in the phagosome while also uncovering general principles about how cells balance the need for speed with accuracy when adapting to new environments.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.