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Restoring airway epithelial homeostasis in Cystic Fibrosis

Published:October 07, 2022DOI:https://doi.org/10.1016/j.jcf.2022.09.009

      Highlights

      • CFTR dysfunction “per se” perturbs epithelial homeostasis.
      • Alternative approaches to high efficiency modulator therapy are promising for CF.
      • Airway rehydration is a Host-Directed Strategies alternative approach for CF.
      • Phage therapy is a Pathogen-Directed Strategies (PDS) alternative approach for CF.

      Abstract

      Cystic fibrosis (CF), the most common life-threatening genetic disorder in Caucasians, is caused by recessive mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene encoding a chloride ion channel. Aberrant function of CFTR involves mucus- and sweat-producing epithelia affecting multiple organs, including airways and lungs. This condition facilitates the colonization of fungi, bacteria, or viruses. Recurrent antibiotic administration is commonly used to treat pathogen infections leading to the insurgence of resistant bacteria and to a chronic inflammatory state that jeopardizes airway epithelium repair. The phenotype of patients carrying CFTR mutations does not always present a strict correlation with their genotype, suggesting that the disease may occur because of multiple additive effects. Among them, the frequent microbiota dysbiosis observed in patients affected by CF, might be one cause of the discrepancy observed in their genotype-phenotype correlation. Interestingly, the abnormal polarity of the CF airway epithelium has been observed also under non-infectious and non-inflammatory conditions, suggesting that CFTR dysfunction “per se” perturbs epithelial homeostasis. New pathogen- or host-directed strategies are thus needed to counteract bacterial infections and restore epithelial homeostasis in individuals with CF. In this review, we summarized alternative cutting-edge approaches to high-efficiency modulator therapy that might be promising for these patients.

      Keywords

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      References

        • Thavamani A.
        • Salem I.
        • Sferra T.J.
        • Sankararaman S.
        Impact of altered gut microbiota and its metabolites in cystic fibrosis.
        Metabolites. 2021;
        • Amaral M.D.
        • Quaresma M.C.
        • Pankonien I.
        What role does cftr play in development, differentiation, regeneration and cancer?.
        Int J Mol Sci. 2020;
        • Portas L.
        • Pereira M.
        • Shaheen S.O.
        • Wyss A.B.
        • London S.J.
        • Burney P.G.J.
        • Hind M.
        • Dean C.H.
        • Minelli C.
        Lung development genes and adult lung function.
        Am J Respir Crit Care Med. 2020; https://doi.org/10.1164/rccm.201912-2338OC
        • Sly P.D.
        • Brennan S.
        • Gangell C.
        • De Klerk N.
        • Murray C.
        • Mott L.
        • Stick S.M.
        • Robinson P.J.
        • Robertson C.F.
        • Ranganathan S.C.
        Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening.
        Am J Respir Crit Care Med. 2009; https://doi.org/10.1164/rccm.200901-0069OC
        • Meyerholz D.K.
        • Stoltz D.A.
        • Gansemer N.D.
        • Ernst S.E.
        • Cook D.P.
        • Strub M.D.
        • Leclair E.N.
        • Barker C.K.
        • Adam R.J.
        • Leidinger M.R.
        • et al.
        Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs.
        Lab Investig. 2018; https://doi.org/10.1038/s41374-018-0026-7
        • Hajj R.
        • Lesimple P.
        • Nawrocki-Raby B.
        • Birembaut P.
        • Puchelle E.
        • Coraux C
        Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis.
        J Pathol. 2007; https://doi.org/10.1002/path.2118
        • Adam D.
        • Roux-Delrieu J.
        • Luczka E.
        • Bonnomet A.
        • Lesage J.
        • Mérol J.C.
        • Polette M.
        • Abély M.
        • Coraux C.
        Cystic fibrosis airway epithelium remodelling: involvement of inflammation.
        J Pathol. 2015; https://doi.org/10.1002/path.4471
        • Badaoui M.
        • Zoso A.
        • Idris T.
        • Bacchetta M.
        • Simonin J.
        • Lemeille S.
        • Wehrle-Haller B.
        • Chanson M.
        Vav3 mediates pseudomonas aeruginosa adhesion to the cystic fibrosis airway Epithelium.
        Cell Rep. 2020; https://doi.org/10.1016/j.celrep.2020.107842
        • Chan H.C.
        • Jiang X.
        • Ruan Y.C.
        Emerging role of cystic fibrosis transmembrane conductance regulator as an epigenetic regulator: linking environmental cues to microRNAs.
        Clin Exp Pharmacol Physiol. 2014; https://doi.org/10.1111/1440-1681.12271
        • Hansen C.R.
        • Pressler T.
        • Høiby N.
        Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience.
        J Cyst Fibros. 2008; https://doi.org/10.1016/j.jcf.2008.06.009
        • Maffioli S.I.
        • Zhang Y.
        • Degen D.
        • Carzaniga T.
        • Del Gatto G.
        • Serina S.
        • Monciardini P.
        • Mazzetti C.
        • Guglierame P.
        • Candiani G.
        • et al.
        Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase.
        Cell. 2017; https://doi.org/10.1016/j.cell.2017.05.042
        • Brown E.D.
        • Wright G.D.
        Antibacterial drug discovery in the resistance era.
        Nature. 2016;
        • Hraiech S.
        • Brégeon F.
        • Rolain J.M.
        Bacteriophage-based therapy in cystic fibrosis-associated Pseudomonas aeruginosa infections: rationale and current status.
        Drug Des Dev Ther. 2015;
        • Schooley R.T.
        • Biswas B.
        • Gill J.J.
        • Hernandez-Morales A.
        • Lancaster J.
        • Lessor L.
        • Barr J.J.
        • Reed S.L.
        • Rohwer F.
        • Benler S.
        • et al.
        Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant acinetobacter baumannii infection.
        Antimicrob Agents Chemother. 2017; : 61https://doi.org/10.1128/AAC.00954-17
        • Aslam S.
        • Lampley E.
        • Wooten D.
        • Karris M.
        • Benson C.
        • Strathdee S.
        • Schooley R.T.
        Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States.
        Open Forum Infect Dis. 2020; https://doi.org/10.1093/ofid/ofaa389
        • Law N.
        • Logan C.
        • Furr C.
        • Lehman S.
        • Morales S.
        • Rosas F.
        • et al.
        Successful bacteriophage therapy for treatment of multidrug-resistant pseudomonas aeruginosa infection in a cystic fibrosis patient.
        J Hear Lung Transplant. 2019; 38: S38https://doi.org/10.1016/j.healun.2019.01.078
        • Dedrick R.M.
        • Guerrero-Bustamante C.A.
        • Garlena R.A.
        • Russell D.A.
        • Ford K.
        • Harris K.
        • Gilmour K.C.
        • Soothill J.
        • Jacobs-Sera D.
        • Schooley R.T.
        • et al.
        Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus.
        Nat Med. 2019; 25: 730-733https://doi.org/10.1038/s41591-019-0437-z
        • Morrison K.D.
        • Underwood J.C.
        • Metge D.W.
        • Eberl D.D.
        • Williams L.B.
        Mineralogical variables that control the antibacterial effectiveness of a natural clay deposit.
        Environ Geochem Health. 2014; https://doi.org/10.1007/s10653-013-9585-0
        • Morrison K.D.
        • Martin K.A.
        • Wimpenny J.B.
        • Loots G.G.
        Synthetic antibacterial minerals: harnessing a natural geochemical reaction to combat antibiotic resistance.
        Sci Rep. 2022; https://doi.org/10.1038/s41598-022-05303-x
        • Chawla M.
        • Verma J.
        • Gupta R.
        Antibiotic potentiators against multidrug-resistant bacteria: discovery, development, and clinical relevance.
        Front Microbiol. 2022; 1: 88725https://doi.org/10.3389/fmicb.2022.887251
        • Yu B.
        • Roy Choudhury M.
        • Yang X.
        • Benoit S.L.
        • Womack E.
        • Van Mouwerik Lyles K.
        • Acharya A.
        • Kumar A.
        • Yang C.
        • Pavlova A.
        • Zhu M.
        • Yuan Z.
        • Gumbart J.C.
        • Boykin D.W.
        • Maier R.J.
        • Eichenbaum Z.
        Restoring and enhancing the potency of existing antibiotics against drug-resistant gram-negative bacteria through the development of potent small-molecule adjuvants.
        ACS Infect Dis. 2022; https://doi.org/10.1021/acsinfecdis.2c00121
        • Visaggio D.
        • Frangipani E.
        • Hijazi S.
        • Pirolo M.
        • Leoni L.
        • Rampioni G.
        • Imperi F.
        • Bernstein L.
        • Sorrentino R.
        • Ungaro F.
        • et al.
        Variable Susceptibility to gallium compounds of major cystic fibrosis pathogens.
        ACS Infect Dis. 2022; https://doi.org/10.1021/acsinfecdis.1c00409
        • Zumla A.
        • Rao M.
        • Wallis R.S.
        • Kaufmann S.H.E.
        • Rustomjee R.
        • Mwaba P.
        • Vilaplana C.
        • Yeboah-Manu D.
        • Chakaya J.
        • Ippolito G.
        • et al.
        Host-directed therapies for infectious diseases: current status, recent progress, and future prospects.
        Lancet Infect Dis. 2016;
        • Saint-Criq V.
        • Gray M.A.
        Role of CFTR in epithelial physiology.
        Cell Mol Life Sci. 2017;
        • Ruan Y.C.
        • Wang Y.
        • da Silva N.
        • Kim B.
        • Diao R.Y.
        • Hill E.
        • Brown D.
        • Chan H.C.
        • Breton S.
        CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway.
        J Cell Sci. 2014; https://doi.org/10.1242/jcs.148098
        • Higgins G.
        • Torre C.F.
        • Tyrrell J.
        • McNally P.
        • Harvey B.J.
        • Urbach V.
        Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa.
        Am J Physiol - Lung Cell Mol Physiol. 2016; https://doi.org/10.1152/ajplung.00368.2015
        • Boucher R.C.
        Cystic fibrosis: a disease of vulnerability to airway surface dehydration.
        Trends Mol Med. 2007; https://doi.org/10.1016/j.molmed.2007.05.001
        • Simonin J.L.
        • Luscher A.
        • Losa D.
        • Badaoui M.
        • van Delden C.
        • Köhler T.
        Surface hydration protects cystic fibrosis airways from infection by restoring junctional networks.
        Cells. 2022; 9: 15https://doi.org/10.3390/cells11091587
        • LeSimple P.
        • Liao J.
        • Robert R.
        • Gruenert D.C.
        • Hanrahan J.W.
        Cystic fibrosis transmembrane conductance regulator trafficking modulates the barrier function of airway epithelial cell monolayers.
        J Physiol. 2010; https://doi.org/10.1113/jphysiol.2009.182246
        • Nilsson H.E.
        • Dragomir A.
        • Lazorova L.
        • Johannesson M.
        • Roomans G.M.
        CFTR and tight junctions in cultured bronchial epithelial cells.
        Exp Mol Pathol. 2010; https://doi.org/10.1016/j.yexmp.2009.09.018
        • Castellani S.
        • Guerra L.
        • Favia M.
        • Di Gioia S.
        • Casavola V.
        • Conese M.
        NHERF1 and CFTR restore tight junction organisation and function in cystic fibrosis airway epithelial cells: role of ezrin and the RhoA/ROCK pathway.
        Lab. Investig. 2012; https://doi.org/10.1038/labinvest.2012.123
        • Vitzthum C.
        • Clauss W.G.
        • Fronius M
        Mechanosensitive activation of CFTR by increased cell volume and hydrostatic pressure but not shear stress.
        Biochim Biophys Acta - Biomembr. 2015; https://doi.org/10.1016/j.bbamem.2015.09.009
        • Zhang W.K.
        • Wang D.
        • Duan Y.
        • Loy M.M.T.
        • Chan H.C.
        • Huang P.
        Mechanosensitive gating of CFTR.
        Nat Cell Biol. 2010; https://doi.org/10.1038/ncb2053
        • Xie C.
        • Cao X.
        • Chen X.
        • Wang D.
        • Zhang W.K.
        • Sun Y.
        • Hu W.
        • Zhou Z.
        • Wang Y.
        • Huang P.
        Mechanosensitivity of wild-type and G551D cystic fibrosis transmembrane conductance regulator (CFTR) controls regulatory volume decrease in simple epithelia.
        FASEB J. 2016; https://doi.org/10.1096/fj.15-283002
        • Citi S.
        The mechanobiology of tight junctions.
        Biophys Rev. 2019;
        • Brix A.
        • Cafora M.
        • Aureli M.
        • Pistocchi A.
        Animal models to translate phage therapy to human medicine.
        Int J Mol Sci. 2020;
        • Danis-Wlodarczyk K.
        • Vandenheuvel D.
        • Jang H.Bin
        • Briers Y.
        • Olszak T.
        • Arabski M.
        • Wasik S.
        • Drabik M.
        • Higgins G.
        • Tyrrell J.;.
        • et al.
        A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections.
        Sci Rep. 2016; https://doi.org/10.1038/srep28115
        • Nordstrom H.R.
        • Evans D.R.
        • Finney A.G.
        • Westbrook K.J.
        • Zamora P.F.
        • Iovleva A.
        • Yassin M.H.
        • Bomberger J.M.
        • Shields R.K.
        • Doi Y.
        • et al.
        Genomic and functional characterization of Pseudomonas aeruginosa-targeting bacteriophages isolated from hospital wastewater.
        iScience. 2022; 10 (25(6)): 1https://doi.org/10.1016/j.isci.2022.104372
        • Luscher A.
        • Simonin J.
        • Falconnet L.
        • Valot B.
        • Hocquet D.
        • Chanson M.
        • Resch G.
        • Köhler T.
        • van Delden C.
        Combined bacteriophage and antibiotic treatment prevents pseudomonas aeruginosa infection of wild type and cftr- epithelial cells.
        Front Microbiol. 2020; https://doi.org/10.3389/fmicb.2020.01947
        • Trend S.
        • Chang B.J.
        • O'Dea M.
        • Stick S.M.
        • Kicic A
        Use of a primary epithelial cell screening tool to investigate phage therapy in cystic fibrosis.
        Front Pharmacol. 2018; https://doi.org/10.3389/fphar.2018.01330
        • Alemayehu D.
        • Casey P.G.
        • Mcauliffe O.
        • Guinane C.M.
        • Martin J.G.
        • Shanahan F.
        • Coffey A.
        • Ross R.P.
        • Hill C.
        Bacteriophages φMR299-2 and φNH-4 can eliminate Pseudomonas aeruginosa in the murine lung and on cystic fibrosis lung airway cells.
        MBio. 2012; https://doi.org/10.1128/mBio.00029-12
        • Novoa B.
        • Figueras A.
        Zebrafish: model for the study of inflammation and the innate immune response to infectious diseases.
        Adv Exp Med Biol. 2012; 946: 253-275https://doi.org/10.1007/978-1-4614-0106-3_15
        • Phennicie R.T.
        • Sullivan M.J.
        • Singer J.T.
        • Yoder J.A.
        • Kim C.H.
        Specific resistance to Pseudomonas aeruginosa infection in zebrafish is mediated by the cystic fibrosis transmembrane conductance regulator.
        Infect Immun. 2010; https://doi.org/10.1128/IAI.00302-10
        • Cafora M.
        • Deflorian G.
        • Forti F.
        • Ferrari L.
        • Binelli G.
        • Briani F.
        • Ghisotti D.
        • Pistocchi A
        Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model.
        Sci Rep. 2019; https://doi.org/10.1038/s41598-018-37636-x
        • Johansen M.D.
        • Alcaraz M.
        • Dedrick R.M.
        • Roquet-Banères F.
        • Hamela C.
        • Hatfull G.F.
        • Kremer L
        Mycobacteriophage-antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus.
        DMM Dis. Model. Mech. 2021; https://doi.org/10.1242/dmm.049159
        • Schultz A.
        • Stick S.
        Early pulmonary inflammation and lung damage in children with cystic fibrosis.
        Respirology. 2015;
        • Semaniakou A.
        • Croll R.P.
        • Chappe V.
        Animal models in the pathophysiology of cystic fibrosis.
        Front Pharmacol. 2019;
        • Cafora M.
        • Brix A.
        • Forti F.
        • Loberto N.
        • Aureli M.
        • Briani F.
        • Pistocchi A
        Phages as immunomodulators and their promising use as anti-inflammatory agents in a cftr loss-of-function zebrafish model.
        J Cyst Fibros. 2021; https://doi.org/10.1016/j.jcf.2020.11.017