Despite over a decade of cystic fibrosis (CF) microbiome research, much remains to be learned about the overall composition, metabolic activities, and pathogenicity of the microbes in CF airways, limiting our understanding of the respiratory microbiome's relation to disease. Systems-level integration and modeling of host-microbiome interactions may allow us to better define the relationships between microbiological characteristics, disease status, and treatment response. In this way, modeling could pave the way for microbiome-based development of predictive models, individualized treatment plans, and novel therapeutic approaches, potentially serving as a paradigm for approaching other chronic infections. In this review, we describe the challenges facing this effort and propose research priorities for a systems biology approach to CF lung disease.

Department for Sustainability Italian National Agency for New Technologies Energy and Sustainable Economic Development Rome Italy

Department of Biology University of Florence Sesto Fiorentino Florence Italy

Department of Medical Microbiology Department of Paediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics University of Washington Seattle WA USA

Department of Pediatrics University of Washington Seattle WA USA; Department of Microbiology University of Washington Seattle WA USA; Center for Clinical and Translational Research Seattle Children's Research Institute Seattle WA USA

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