Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis
BackgroundCFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor–tezacaftor–ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486784/full |
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| author | Hazel Ozuna Hazel Ozuna Dinesh Bojja Santiago Partida-Sanchez Luanne Hall-Stoodley Amal Amer Rodney D. Britt Rodney D. Britt Shahid Sheikh David A. Frank Weiyuan Wang Bum-Yong Kang Bum-Yong Kang Irina Miralda Irina Miralda Samantha L. Durfey Samantha L. Durfey Benjamin T. Kopp Benjamin T. Kopp |
| author_facet | Hazel Ozuna Hazel Ozuna Dinesh Bojja Santiago Partida-Sanchez Luanne Hall-Stoodley Amal Amer Rodney D. Britt Rodney D. Britt Shahid Sheikh David A. Frank Weiyuan Wang Bum-Yong Kang Bum-Yong Kang Irina Miralda Irina Miralda Samantha L. Durfey Samantha L. Durfey Benjamin T. Kopp Benjamin T. Kopp |
| author_sort | Hazel Ozuna |
| collection | DOAJ |
| description | BackgroundCFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor–tezacaftor–ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.MethodsWe used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.ResultsThere were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.ConclusionThis study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity. |
| format | Article |
| id | doaj-art-d183dade356f481cb2e95ca7c8653acc |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d183dade356f481cb2e95ca7c8653acc2025-01-28T06:41:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.14867841486784Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosisHazel Ozuna0Hazel Ozuna1Dinesh Bojja2Santiago Partida-Sanchez3Luanne Hall-Stoodley4Amal Amer5Rodney D. Britt6Rodney D. Britt7Shahid Sheikh8David A. Frank9Weiyuan Wang10Bum-Yong Kang11Bum-Yong Kang12Irina Miralda13Irina Miralda14Samantha L. Durfey15Samantha L. Durfey16Benjamin T. Kopp17Benjamin T. Kopp18Center for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University School of Medicine, Atlanta, GA, United StatesDivision of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United StatesYale University, New Haven, CT, United StatesThe Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesThe Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesDepartment of Pediatrics, The Ohio State University, Columbus, OH, United StatesThe Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United StatesWinship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United StatesWinship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United StatesCenter for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University School of Medicine, Atlanta, GA, United StatesDivision of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United StatesCenter for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University School of Medicine, Atlanta, GA, United StatesDivision of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United StatesCenter for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University School of Medicine, Atlanta, GA, United StatesDivision of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United StatesCenter for Cystic Fibrosis and Airways Disease Research (CF-AIR), Emory University School of Medicine, Atlanta, GA, United StatesDivision of Pulmonology, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United StatesBackgroundCFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor–tezacaftor–ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.MethodsWe used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.ResultsThere were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.ConclusionThis study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486784/fullcystic fibrosisinflammationproteomicsmodulatorsNF-κB |
| spellingShingle | Hazel Ozuna Hazel Ozuna Dinesh Bojja Santiago Partida-Sanchez Luanne Hall-Stoodley Amal Amer Rodney D. Britt Rodney D. Britt Shahid Sheikh David A. Frank Weiyuan Wang Bum-Yong Kang Bum-Yong Kang Irina Miralda Irina Miralda Samantha L. Durfey Samantha L. Durfey Benjamin T. Kopp Benjamin T. Kopp Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis Frontiers in Immunology cystic fibrosis inflammation proteomics modulators NF-κB |
| title | Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis |
| title_full | Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis |
| title_fullStr | Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis |
| title_full_unstemmed | Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis |
| title_short | Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis |
| title_sort | proteomics profiling of inflammatory responses to elexacaftor tezacaftor ivacaftor in cystic fibrosis |
| topic | cystic fibrosis inflammation proteomics modulators NF-κB |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1486784/full |
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