Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation

Harris, J. Kirk; Wagner, Brandie D.; Zemanick, Edith T.; Robertson, Charles E.; Stevens, Mark J.; Heltshe, S.; Rowe, Steven M.; Sagel, Scott D.

doi:10.1513/annalsats.201907-493oc

Cited by 128 publications

(98 citation statements)

References 18 publications

(27 reference statements)

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“…Second, we performed our analysis at a single time point after treatment, and thus our data capture an early snapshot of acute changes in monocytes after initiation of ivacaftor, which may not reflect chronic therapy. Most studies evaluating changes in cells and biomarkers following initiation of CFTR modulators have sampled subjects at only one time point, with few longitudinal studies ( Rowe et al., 2014 ; Hisert et al., 2017 ; Ronan et al., 2018 ; Kopp et al., 2019 ; Sun et al., 2019 ; Harris et al., 2020 ); however, the synthesis of individual time points with the longitudinal studies suggest that there may be phases of changes in inflammation following restoration of CFTR activity with modulators. The changes reported here occurred within the first week of ivacaftor treatment, and thus reflect acute responses to ivacaftor, and may not reflect a longer term steady-state that incorporates both primary and secondary changes induced by ivacaftor.…”

Section: Discussionmentioning

confidence: 99%

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

et al. 2020

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Background CFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving airway infection and inflammation persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation in the CFTR modulator era require better understanding of cellular contributions to chronic CF airway disease, and how inflammatory cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, represent intriguing cellular targets for focused therapies. This therapeutic approach, however, requires a more detailed knowledge of CF monocyte cellular programming and phenotypes. Material and Methods In order to characterize the inflammatory phenotype of CF monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq) followed by pathway-based analyses. Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional programs were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including biological modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. Conclusions Our results demonstrate that ivacaftor causes acute changes in blood monocyte transcriptional profiles and plasma chemokines, and suggest that increased monocyte inflammatory signals and changes in myeloid cell trafficking may contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of circulating blood monocytes in CF subjects treated with a CFTR modulator.

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Section: Discussionmentioning

confidence: 99%

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

et al. 2020

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“…However, early and sustained use of new CFTR modulators may help reverse potential alterations in macrophage inflammatory responses that adversely impact CF outcomes. Prior studies of first-generation CFTR modulators have not shown sustained reductions in sputum inflammatory markers (51,52). New investigations into early immune responses in CF are the focus of several ongoing studies around the globe.…”

Section: Discussionmentioning

confidence: 99%

Consequences of CRISPR-Cas9-Mediated CFTR Knockout in Human Macrophages

et al. 2020

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Macrophage dysfunction is fundamentally related to altered immunity in cystic fibrosis (CF). How genetic deficits in the cystic fibrosis transmembrane conductance regulator (CFTR) lead to these defects remains unknown. Rapid advances in genomic editing such as the clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) system provide new tools for scientific study. We aimed to create a stable CFTR knockout (KO) in human macrophages in order to study how CFTR regulates macrophage function. Peripheral blood monocytes were isolated from non-CF healthy volunteers and differentiated into monocyte-derived macrophages (MDMs). MDMs were transfected with a CRISPR Cas9 CFTR KO plasmid. CFTR KO efficiency was verified and macrophage halide efflux, phagocytosis, oxidative burst, apoptosis, and cytokine functional assays were performed. CFTR KO in human MDMs was efficient and stable after puromycin selection. CFTR KO was confirmed by CFTR mRNA and protein expression. CFTR function was abolished in CFTR KO MDMs. CFTR KO recapitulated known defects in human CF MDM (CFTR class I/II variants) dysfunction including (1) increased apoptosis, (2) decreased phagocytosis, (3) reduced oxidative burst, and (4) increased bacterial load. Activation of the oxidative burst via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assembly was diminished in CFTR KO MDMs (decreased phosphorylated p47 phox). Cytokine production was unchanged or decreased in response to infection in CFTR KO MDMs. In conclusion, we developed a primary human macrophage CFTR KO system. CFTR KO mimics most pathology observed in macrophages obtained from persons with CF, which suggests that many aspects of CF macrophage dysfunction are CFTR-dependent and not just reflective of the CF inflammatory milieu.

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“…A recent study demonstrated that six months of ivacaftor treatment was unable to significantly change airway microbiome and several inflammation measurements in patients carrying at least one G551D mutation. Such findings indicate that antibiotics and anti-inflammatory drugs will still be required to control disease symptoms and prevent complications (Harris et al, 2019). As the disease progresses, patients may also develop comorbidities and thus require even more complex therapeutic regimens, adding further burdens.…”

Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Changes in Airway Microbiome and Inflammation with Ivacaftor Treatment in Patients with Cystic Fibrosis and the G551D Mutation

Cited by 128 publications

References 18 publications

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

Consequences of CRISPR-Cas9-Mediated CFTR Knockout in Human Macrophages

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

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