NHLBI and ORD Workshop Host Response to Persistent Bacterial Load in Cystic Fibrosis

Executive Summary

September 12-13, 2005

Chronic infectious airway diseases such as cystic fibrosis are characterized by a scenario that typically reflects poor/absent clearance of mucus, infection of mucus by inhaled bacteria, chronic stimulation of host defenses by persistent bacterial mucus infection, and typically a failure to eradicate the infection due to the failure to clear mucus. In the absence of rectifying the primary defect in mucus clearance, the progression of the disease in the host reflects in part a balance between the effectiveness of the host defense mechanisms to suppress bacterial growth/spread and the destructive effects of “frustrated” host defense mechanisms on the airway wall. In addition, there is usual incidence of intercurrent lower respiratory viral infections in these patients, but the consequences to the host are more severe than in normal individuals. Whereas substantial knowledge is being achieved regarding the sequence of viral followed by bacterial infections in mucosal surfaces, there are relatively few studies of the reverse sequence, i.e., the effect of chronic bacterial infection on an intercurrent viral process.

The overarching goal of the workshop was to provide novel insights into critical new steps in the pathogenesis of diseases of persistent mucus adhesion/infection to yield new and better therapeutic strategies. This workshop reviewed the state of knowledge on: 1) Initiation and mechanism of mucus adhesion to airway surfaces; 2) how bacteria typically infect airways and interact with abnormal mucus to generate persistent infection; 3) how the persistent stimulation of host elements, e.g. epithelium macrophages, lymphocytes, and dendritic cells, leads to a balance between a persistent inflammatory response and tolerance to this antigenic load; and 4) how an airway plagued by chronic bacterial infection responds to intercurrent viral infections, e.g., with paramyxoviruses and rhinoviruses, to create a more adverse outcome to the host. Following evaluation of the current state of knowledge, the workshop participants identified gaps in our knowledge, established the important research questions, and made recommendations for future research directions.

Recommendations:

• New and/or improved treatment strategies aimed at the disadhesing mucus or mucus plaques to mobilize the mucus and foster increased mucociliary clearance are needed;
• The nature of the interactions between viruses and bacteria in CF in initiating events in early development of disease and/or during exacerbation and in chronically colonized conditions requires exploration. Importantly, the mechanisms and players need to be defined, as well as the cellular and molecular processes perturbed, the physical factors in the extracellular environment, the impact of the CF phenotype underlying the infection on viral/bacterial clearance, the synergy between bacteria and viruses in CF versus normals, the role of viruses in exacerbations of CF and progression of CF lung disease, the role of CFTR mutations and modifier genes versus the bacterial environment on CF response to bacterial infection, the role of genetic predisposition/susceptibility to viral infection and first outcome to viral infection, the role of viral infection in enhancing greater susceptibility to bacterial infection and the timing of events, the impact of biofilm formation, and the impact of pre-existing bacterial infection and inflammation on response to virus;
• More insight is needed into the role of mucins in persistence of infection, defining bacterial/viral interactions with mucins and the ability to modulate these interactions, and ability of mucins to facilitate clearance of infections in patients with CF versus normal subjects.
• The role of lipids in CF inflammation and resolution require investigation, including exploring the relationship of the lipid abnormalities to the deficit in CFTR function. Translational studies capitalizing on congeners of these lipids or their receptors need to be pursued;

The meeting was held on September 12-13, 2005 in Rockville, Maryland, USA

Workshop Members

Chair: Richard Boucher, M.D., University of North Carolina , Chapel Hill

Members

• Robert Atmar, M.D., Baylor College of Medicine
• Robert Clarke, Ph.D., Pulmatrx, Inc.
• Pamela Davis, M.D., Ph.D., Case Western Reserve University
• James Gern, M.D., University of Wisconsin, Madison
• Hatti Gresham, Ph.D., University of New Mexico
• Barbara Iglewski, Ph.D., University of Rochester
• Christopher Karp, M.D., Cincinnati Children's Hospital Medical Center
• Steven Lory, Ph.D., Harvard Medical School
• Chris Penland, Ph.D., Cystic Fibrosis Foundation
• Raymond Pickles, Ph.D., University of North Carolina , Chapel Hill
• Scott Randell, Ph.D., University of North Carolina , Chapel Hill
• Michael Rubinstein, Ph.D., University of North Carolina , Chapel Hill
• Bruce Rubin, M.D., Wake Forest University School of Medicine
• Sanjay Sethi, M.D., University of Buffalo
• John Sheehan, Ph.D., University of North Carolina , Chapel Hill
• Pedro Verdugo, M.D., University of Washington
• Thomas Wynn, Ph.D., National Institute of Allergy and Infectious Diseases, NIH

NIH Staff

• Susan Banks-Schlegel, Ph.D., National Heart, Lung, and Blood Institute, NIH
• Stephen Groft, Ph.D., Office of Rare Diseases Research, OD, NIH

February 2006