Advent of elexacaftor/tezacaftor/ivacaftor for cystic fibrosis treatment: What consequences on Aspergillus-related diseases? Preliminary insights

Chesnay, Adélaïde; Bailly, Éric; Cosson, Laure; Flament, Thomas; Désoubeaux, Guillaume

doi:10.1016/j.jcf.2022.09.007

Cited by 5 publications

(4 citation statements)

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“…It is also in line with two recent studies, where a rapid significant decrease in Aspergillus spp. positive sputum cultures and a restoring of dampened Aspergillus -induced reactive oxygen species production by CF phagocytes by CFTR modulators could be shown ( Currie et al, 2020 ; Chesnay et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

et al. 2023

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Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity.Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI.Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly.Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

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Section: Discussionmentioning

confidence: 99%

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

et al. 2023

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“…Encouragingly, a small single-center pilot study of 58 pwCF starting ETI found a reduction in the proportion of sputum cultures positive for Aspergillus sp. and a reduction in total IgE and anti- Aspergillus precipitating antibodies, although specific IgG and IgE antibodies did not decrease [ 90 ]. Ongoing longitudinal studies will provide important additional information, although the reduction in sputum availability must be considered in designing and interpreting all of these studies.…”

Section: Cftr Modulators and Aspergillusmentioning

confidence: 99%

Infection, Allergy, and Inflammation: The Role of Aspergillus fumigatus in Cystic Fibrosis

Poore

Zemanick

2023

Microorganisms

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Aspergillus fumigatus (Af) is a mold frequently detected in airway samples from people with cystic fibrosis (pwCF). Abnormal airway mucus may allow Af to germinate, resulting in airway infection or an allergic response. While Af is known to increase morbidity in pwCF, individual responses and the degree of impact on lung disease vary. Improved approaches to diagnosis, treatment, and prevention of Af, particularly the persistent Af infection, are needed. This update highlights our current understanding of Af pathophysiology in the CF airway, the effects of Af on pwCF, and areas of research needed to improve clinical outcomes.

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“…As people with CF are living longer as a result of therapeutic advances, and as intensive antibiotic suppressive therapy for bacterial infection becomes more common, the incidence and prevalence of A. fumigatus infection has increased over the past decades ( Bargon et al., 1999 ; Valenza et al., 2008 ). The onset of highly effective CFTR modulator therapy has improved pulmonary function and mucociliary clearance in many CF patients, however, beneficial outcomes on fungal infections remain to be seen ( Bercusson et al., 2021 ; Chesnay et al., 2022 ). The effect of colonization or infection with A. fumigatus on CF lung function at the cellular level is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Protective role of CFTR during fungal infection of cystic fibrosis bronchial epithelial cells with Aspergillus fumigatus

Illek,

Fischer,

Machen

et al. 2023

Front. Cell. Infect. Microbiol.

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Lung infection with the fungus Aspergillus fumigatus (Af) is a common complication in cystic fibrosis (CF) and is associated with loss of pulmonary function. We established a fungal epithelial co-culture model to examine the impact of Af infection on CF bronchial epithelial barrier function using Af strains 10AF and AF293-GFP, and the CFBE41o- cell line homozygous for the F508del mutation with (CF+CFTR) and without (CF) normal CFTR expression. Following exposure of the epithelial surface to Af conidia, formation of germlings (early stages of fungal growth) was detected after 9-12 hours and hyphae (mature fungal growth) after 12-24 hours. During fungal morphogenesis, bronchial epithelial cells showed signs of damage including rounding, and partial detachment after 24 hours. Fluorescently labeled conidia were internalized after 6 hours and more internalized conidia were observed in CF compared to CF+CFTR cells. Infection of the apical surface with 10AF conidia, germlings, or hyphae was performed to determine growth stage-specific effects on tight junction protein zona occludens protein 1 (ZO-1) expression and transepithelial electrical resistance (TER). In response to infection with conidia or germlings, epithelial barrier function degraded time-dependently (based on ZO-1 immunofluorescence and TER) with a delayed onset in CF+CFTR cell monolayers and required viable fungi and apical application. Infection with hyphae caused an earlier onset and faster rate of decline in TER compared to conidia and germlings. Gliotoxin, a major Af virulence factor, caused a rapid decline in TER and induced a transient chloride secretory response in CF+CFTR but not CF cells. Our findings suggest growth and internalization of Af result in deleterious effects on bronchial epithelial barrier function that occurred more rapidly in the absence of CFTR. Bronchial epithelial barrier breakdown was time-dependent and morphotype-specific and mimicked by acute administration of gliotoxin. Our study also suggests a protective role for CFTR by turning on CFTR-dependent chloride transport in response to gliotoxin, a mechanism that will support mucociliary clearance, and could delay the loss of epithelial integrity during fungal development in vivo.

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Advent of elexacaftor/tezacaftor/ivacaftor for cystic fibrosis treatment: What consequences on Aspergillus-related diseases? Preliminary insights

Cited by 5 publications

References 5 publications

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

Infection, Allergy, and Inflammation: The Role of Aspergillus fumigatus in Cystic Fibrosis

Protective role of CFTR during fungal infection of cystic fibrosis bronchial epithelial cells with Aspergillus fumigatus

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