INSPIRE: How Do Cilia-driven Flows Shape the Chemical and Mechanical Environment in Bacteria-Host Associations?

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This is an INSPIRE award that was co-funded by the Biosciences Directorate, Division of Molecular and Cellular Biosciences (MCB), Systems and Synthetic Biology (SSB) program, and the Engineering Directorate, Division of Civil, Mechanical, and Manufacturing Innovation (CMMI), Dynamics, Control and System Diagnostics (DCSD) program. Beneficial and pathogenic bacteria alike, commonly interact with host cells along mucosal epithelia. These surfaces are often lined with dense fields of motile cilia that serve both a biomechanical function for generating mucociliary flows, and a biochemical function to detect and present molecular signals. The goal of this project is to investigate a the dynamic association of healthy and diseased ciliated tissues. The project posits that cilia-generated flows influence bacteria-host interactions, thereby challenging the conventional view in biology that attributes bacterial recruitment mostly to active bacterial behavior and passive diffusion, ignoring the effect of cilia-generated flows on both motility and mass transport. The broader impacts of this study are that this project provides excellent educational and training opportunities at the intersection of disciplines, while also generating new insight in microbial host colonization that are likely to reveal avenues for impactful strategies to block pathogenic bacteria from colonizing the host, while enhancing the colonization potential of beneficial organisms.The approach incorporates interdisciplinary methods, ranging from cutting-edge imaging and genetic tools to novel microfluidic technologies, all combined with powerful mathematical and computational framework, to investigate this fundamental problem in bacteria-host associations, namely, the role of cilia-generated flows in shaping these associations. The project will build a quantitative and predictive model that is informed by experimental assays in two complementary model systems:1. In vivo invertebrate model: the squid-vibrio system, an intact animal host operating in its natural fluid environment, will be used to study how the host's ciliated epithelium initiates contact with its native, flow-borne bacterial community. Events in the squid-vibrio association share remarkable similarities with host responses to human-relevant pathogens, while still being accessible to imaging and experimental manipulation.2. In silico microfluidics: properly designed microfluidic channels will be used as a tool to analyze the response of bacterial cells to carefully controlled microenvironment. This approach is aimed at complementing the squid-vibrio studies by providing a platform that isolates the chemical gradients and flow shear gradients observed in the in vivo model, thus allowing to unravel the mechanisms dictating bacterial behavior and possibly triggering the changes in bacterial gene expressions causing the transition from free-swimming to biofilm state.