Characterizing Population Heterogeneity of Salmonella Motion in Mucosal Environments Using Stochastic Modeling and the EM Algorithm

Abstract

Salmonella are pathogenic bacteria that infect many species including humans. This pathogen thrives in the gastrointestinal track of their hosts and propel themselves in mucus with motion structures called flagella. Each cell has multiple flagella that can rotate either synchronously, resulting in directed motion, or asynchronously. This creates a distinct motion pattern known as “run and tumble” motion. A large particle tracking dataset of Salmonella in mucus harvested from mouse GI tract was recently published by Schroeder et al. [28]. This dataset includes a substantial fraction of cells that exhibit exclusively undirected motion while other cells exhibit exclusively run-and-tumble-type motion patterns. It is well known that Salmonella experience a significant amount of population heterogeneity in order to evade host immune cells, and this heterogeneity can manifest in motion patterns through its impact on flagella number and type. A systematic and quantitative statistical analysis of the Schroeder et al. dataset, informed by mechanistic stochastic models of cell motion, is performed to characterize motion heterogeneity. It is found that two distinct populations can be characterized that emerge from a rigorous statistical optimization procedure called Expectation Maximization. These two populations are described as “diffusers” and “swimmers.” Interestingly, cells in the diffusers populations display random switching between distinct diffusivity values that differ by nearly 10 fold, indicating a previously unknown source of active motion among these otherwise non-motile cells. Approximately 8% of tracks were estimated to switch between these two subpopulations, most of which were attributable to tracking errors or uncertainty due to short track lengths. It is speculated that the remaining handful of tracks, which all transition from diffusers to swimmers, could be explained by young cells reaching the stage of development where they are able to generate directed motion.