Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY / ABSTRACT Despite the recent surge in studies reporting on the prevalence and abundance of anaerobic microbiota in the airways of individuals with cystic fibrosis (CF), their mechanistic contributions, if any, to disease pathophysiology remain controversial and poorly understood. This knowledge gap is driven, in part, by conflicting epidemiological and in vitro experimental data, a lack of suitable model systems to study their interactions with the host, and the dearth of laboratory expertise in host-associated anaerobic microbiology. Studies that generate greater insight into the role of anaerobes in CF lung infection, particularly at early stages, are necessary to determine if, when, and how to target this group of organisms therapeutically. Our team has shown that (i) anaerobes are early colonizers of the pediatric CF airways prior to the acquisition of canonical pathogens, (ii) anaerobe bacterial communities elicit pro-inflammatory response when co-cultured with bronchial epithelial cells, and (iii) anaerobe-mediated mucin degradation and cross- feeding can shape the growth, virulence, and antibiotic susceptibility of canonical CF pathogens. Building on these data, this project proposes to use a multi-disciplinary approach to investigate how individual anaerobes interact with one another, the airway epithelium, and traditional pathogens (e.g., P. aeruginosa, S. aureus) in the context of early CF airway disease. First, using an experimental microbiome model system composed of 10 CF anaerobic species, we will determine how CF bacterial communities assemble and how their assembly dynamics are shaped by host and microbial processes. Second, using an innovative dual oxic-anoxic system that enables co-culture of anaerobic bacteria and airway epithelial cells, we will use single-cell RNA sequencing to determine how anaerobes interact with the airway epithelium, and how the host response varies by epithelial cell type. Finally, given that P. aeruginosa, S. aureus, and other aerobic pathogens co-colonize with anaerobic microbiota and rapidly adapt to the airways as patients age, we will use an in vitro experimental evolution approach to test whether early CF microbiota are sufficient to drive the adaptation of canonical pathogens to the nutritional milieu of the CF airways. At the completion of these aims, we will have defined how individual anaerobes interact with one another, the host, and traditional CF pathogens. In doing so, these studies will have a meaningful impact on our mechanistic understanding of the role of airway microbiota in chronic airway disease and may motivate future studies targeting specific anaerobic bacteria, or even promoting their growth, as a means of improving clinical outcomes. Finally, we use CF as our model system, but this work is broadly applicable to other acute and airway infections (e.g., COPD, sinusitis, ventilator associated pneumonias) in which anaerobes have been implicated but their mechanistic contributions remain undefined.
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