Adaptations of bacterial communities during chronic infections can increase inflammation while limiting innate immune system clearance. In CF airways, decreased lung function correlates with; age, accumulation of neutrophils, thickening of the reticular basement membrane wall; all leading to decreased lung function. Studies using in vitro pathogenesis models have identified several proinflammatory responses by using single isolates of bacterial pathogens. Despite the knowledge of host adaptation and the emergence of genetic variants in microbial populations during chronic infections, the impact of this intra-specific population heterogeneity on pathogenesis is overlooked due to challenges in capturing intra-specific genetic heterogeneity and lack of a robust in vitro experimental framework. Thus, there is a gap in knowledge regarding the impact of bacterial population spatial organization on host responses, microbe-microbe interactions, niche specification, and the biogeography of CF airways.