Chronic Inflammation in Adult Cystic Fibrosis Patients

Determining whether specific bacterial products from CF isolates are toxic or induce an inflammatory response

Full Project Name:Bacterial Products Related to Chronic Inflammation in Adult Cystic Fibrosis PatientsPrincipal Investigator:Dara W. Frank, PhD, Microbiology and ImmunologyCo-Investigator:Julie A. Biller, MD, Medicine; Nathan A. Ledeboer, PhD, PathologyAward Amount:$200,000

Award Date

February2017

Project Duration:24 months

Project Description Narrative:

Patients with cystic fibrosis (CF) develop chronic inflammatory pneumonia related to life-long infections with bacterial pathogens. To reduce the pathology and bacterial load, individuals with CF are frequently treated with antibiotics, resulting in selection of pan-resistant, colonizing bacteria. Genome sequences, now available for opportunistic pathogens that colonize the CF lung, have revealed genes for bacterial products that may contribute to inflammation and cycles of exacerbation and lung damage.

Through this award, the research team seeks to determine whether specific bacterial products are contributing to inflammation and cycles of exacerbation and lung damage in CF patients with the ultimate goal of identifying effective therapies and treatments.

Outcomes & Lessons Learned:

Identified specific genes and pathways that may contribute to macrophage toxicity, which may significantly enhance the inflammatory response and contribute to chronic lung damage
Determined that some groups of Achromobacter xlyosoxidans (Ax), a previously overlooked organism that is resistant to many antibiotics, may be an important diagnostic variable in the treatment of CF, especially as patients age
Further analyses utilizing tools developed through this project will not only clarify the roles of certain bacterial products in lung pathology, but also provide targets for therapeutic development
Presented research at ten local and regional conferences and currently preparing one manuscript for submission

Project Updates:

• Tested several cell lines, finding that A. xylosoxidans infects and kills macrophage-like cells and does not seem to infect epithelial cells. This represents the development of the first cellular model of infection for A. xylosoxidans• Produced recombinant antigens for the toxin and for a few of the type 3 secretion system proteins that may be most prominent on the bacterial surface• Completed sequencing of two genomes from isolates that have different in-vitro cellular pathology outcomes. Annotation of both genomes is in-process• Preliminary data suggest that A. xylosoxidans may contribute to lung pathology in adult CF patients by injecting a type III protein that is cytotoxic. The specific infection of macrophage-like cell lines may be significant