The Infectious Dose Shapes Vibrio cholerae Within-Host Dynamics

Abstract

ABSTRACT During infection, the rates of pathogen replication, death, and migration affect disease progression, dissemination, transmission, and resistance evolution. Here, we follow the population dynamics of Vibrio cholerae in a mouse model by labeling individual bacteria with one of >500 unique, fitness-neutral genomic tags. Using the changes in tag frequencies and CFU numbers, we inform a mathematical model that describes the within-host spatiotemporal bacterial dynamics. This allows us to disentangle growth, death, forward, and retrograde migration rates continuously during infection. Our model has robust predictive power across various experimental setups. The population dynamics of V. cholerae shows substantial spatiotemporal heterogeneity in replication, death, and migration. Importantly, we find that the niche available to V. cholerae in the host increases with inoculum size, suggesting cooperative effects during infection. Therefore, it is not enough to consider just the likelihood of exposure (50% infectious dose) but rather the magnitude of exposure to predict outbreaks. IMPORTANCE Determining the rates of bacterial migration, replication, and death during infection is important for understanding how infections progress. Separately measuring these rates is often difficult in systems where multiple processes happen simultaneously. Here, we use next-generation sequencing to measure V. cholerae migration, replication, death, and niche size along the mouse gastrointestinal tract. We show that the small intestine of the mouse is a heterogeneous environment, and the population dynamic characteristics change substantially between adjacent gut sections. Our approach also allows us to characterize the effect of inoculum size on these processes. We find that the niche size in mice increases with the infectious dose, hinting at cooperative effects in larger inocula. The dose-response relationship between inoculum size and final pathogen burden is important for the infected individual and is thought to influence the progression of V. cholerae epidemics.

Keywords

• founder population size
• moment closure
• particle swarm optimization
• stochastic spatiotemporal population dynamics
• dose response
• Vibrio cholerae