Cystic Fibrosis (CF) is a genetic disorder affecting thousands in the United States and worldwide. Loss of function mutations in the CF transmembrane conductance regulator (CFTR), a chloride ion channel, results in abnormal maintenance of airway surface liquid and loss of mucociliary clearance. CF patients suffer from chronic bacterial infection in the lung with limited therapeutic recourse. Staphylococcus aureus is an important Gram-positive organism in the context of CF. With the increasing prevalence of methicillin-resistant S. aureus (MRSA), this bacterium will likely play a greater role in CF pathogenesis in the near future. MRSA colonization is associated with greater declines in lung function in CF and may influenza polymicrobial infections often found in this disease. Our laboratory has previously demonstrated an important role for Type 17 immunity in regulating S. aureus host defense. Type 17 cytokines, IL-17 and IL-22, stimulate antimicrobial peptide production by epithelial cells that are critical to S. aureus clearance. At this time, it is unclear if Type 17 or related antimicrobial responses are aberrant in the context of CF. Further, preceding viral infection increases susceptibility to S. aureus infection by suppressing anti-bacterial Type 17 immunity. Viral exacerbation in CF is associated with acquisition of bacterial infection. For these reasons we propose that CFTR deficient epithelial cells display attenuated responses to Type 17 cytokines resulting in worsened S. aureus infection and that influenza co-infection exacerbates S. aureus carriage. This hypothesis will be tested in two specific aims. First, we will investigate S. aureus biofilm growth on human airway epithelial cells from CF and control patients and the impact of Type 17 cytokines on colonization. Second, we will characterize the Type 17 immune response during nasal S. aureus infection in a murine nasal epithelial model of CF and examine how influenza affects S. aureus carriage. The proposed studies will examine the Type 17 immune response during S. aureus infection and how influenza co-infection affects S. aureus growth in CF. These studies will help clarify host-pathogen interactions in CF and characterize the relationship between two important respiratory pathogens that contribute to a decline in lung function in CF patients.

Public Health Relevance

Cystic Fibrosis (CF) is a disorder characterized by progressive lung injury associated with bacterial and viral infection. Molecular mechanisms regulating host defense to Staphylococcus aureus in the context of CF is lacking. The goal of this study is to determine novel mediators of S. aureus clearance and determine deficiency in CF that predispose to chronic infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
2P30DK072506-11
Application #
8875233
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2005-09-15
Project End
2018-05-31
Budget Start
2015-07-01
Budget End
2016-05-31
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gopal, Radha; Rapaka, Rekha R; Kolls, Jay K (2017) Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev 26:
Wu, Tongde; Huang, Julianne; Moore, Patrick J et al. (2017) Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor. Nat Commun 8:14118
Corcoran, Timothy E; Godovchik, Joseph E; Donn, Karl H et al. (2017) Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis. Pediatr Pulmonol 52:1142-1149
Guerriero, Christopher J; Reutter, Karl-Richard; Augustine, Andrew A et al. (2017) Transmembrane helix hydrophobicity is an energetic barrier during the retrotranslocation of integral membrane ERAD substrates. Mol Biol Cell 28:2076-2090
Manni, Michelle L; Mandalapu, Sivanarayana; Salmeron, Andres et al. (2017) Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease. Sci Rep 7:43139
Chakraborty, Krishnendu; Raundhal, Mahesh; Chen, Bill B et al. (2017) The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun 8:13944
Flitter, Becca A; Hvorecny, Kelli L; Ono, Emiko et al. (2017) Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. Proc Natl Acad Sci U S A 114:136-141
Chen, Kong; Kolls, Jay K (2017) Interluekin-17A (IL17A). Gene 614:8-14
Sharma, Ramankur; Corcoran, Timothy E; Garoff, Stephen et al. (2017) Transport of a partially wetted particle at the liquid/vapor interface under the influence of an externally imposed surfactant generated Marangoni stress. Colloids Surf A Physicochem Eng Asp 521:49-60
Fercana, George R; Yerneni, Saigopalakrishna; Billaud, Marie et al. (2017) Perivascular extracellular matrix hydrogels mimic native matrix microarchitecture and promote angiogenesis via basic fibroblast growth factor. Biomaterials 123:142-154

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