CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons

Zhang, Xi; Moore, Camille M.; Harmacek, Laura; Domenico, Joanne; Rangaraj, Vittobai Rashika; Knapp, Jennifer R.; Woods, Katherine; Jump, Stephanie; Song, Jia; Prokop, Jeremy W.; Bowler, Russell P.; Hessner, Martin J.; Gelfand, Erwin W.; Levy, Hara

doi:10.1172/jci.insight.152186

Cited by 9 publications

(10 citation statements)

References 82 publications

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“…Lipid peroxidation is a hallmark of CF 70,71 and ferroptosis was recently described in CF epithelial cells 72–74 . Our study expands the current understanding of how P. aeruginosa can induce ferroptosis in CF, showing that 1) multidrug-resistant P. aeruginosa can induce ferroptosis in macrophages, one of the most important cell types in bacterial clearance 4–7 , and 2) RNase E variants can confer bacterial hypervirulence by triggering host cell ferroptosis. Since both ferroptosis and dysfunctional macrophages lead to exacerbated inflammation and tissue damage, it is imperative to develop therapeutics that will target this process and protect host cells.…”

Section: Discussionsupporting

confidence: 58%

A Compensatory RNase E Variation Increases Iron Piracy and Virulence in Multidrug-ResistantPseudomonas aeruginosaduring Macrophage Infection

Vaillancourt

Galdino

Limsuwannarot

et al. 2022

Preprint

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During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased siderophore gene expression, causing macrophage ferroptosis and lysis. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

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Section: Discussionsupporting

confidence: 58%

A Compensatory RNase E Variation Increases Iron Piracy and Virulence in Multidrug-ResistantPseudomonas aeruginosaduring Macrophage Infection

Vaillancourt

Galdino

Limsuwannarot

et al. 2022

Preprint

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“…It is important to point out the cell abundance analysis tool AImmune employed here is developed in-house and there is still room for improvement. Although this tool underwent robust testing and validation in our previous studies [27][28][29], the current version is only designed to cover up to 10 immune cell subsets from peripheral blood. This coverage limit is partially due to its nature as AImmune was trained and developed to profile circulating blood samples while other computational immune profiling tools including CIBERSORTx [26,68] and TIMER [69] are often employed to enumerate tumor-infiltrating cells in tissue-dependent microenvironments.…”

Section: Discussionmentioning

confidence: 99%

“…The immune cell abundance change was further elucidated by in silico leukocyte deconvolution approach adopted from our previous work (AImmune) [27][28][29] as well as a classic machine learning tool CIBERSORTx [26] (Supplementary Figure S8 & S9). In agreement with the GSEA results, a significant composition decrease in monocytes and a sturdy increase of DCs were observed in AImmune (Figure 5C, Supplementary Figure S8) while a substantial increase of resting memory CD4+ and CD8+ T lymphocytes were demonstrated in CIBERSORTx (Figure 5D, Supplementary Figure S9).…”

Section: Pd-1-mediated Pathways and Regulatory T Cells Are Distinct S...mentioning

confidence: 99%

“…In the present study, a comprehensive analysis workflow was constructed to identify multi-level biomarker signatures using the transcriptomic profiles of whole blood from a discovery cohort and followed by validations in published datasets or an independent cohort. This workflow utilized well-recognized computational tools including in silico deconvolution approaches developed to profile tumor-infiltrating immune cells in tissue [25,26] and validated on PBMC samples in our prior studies [27][28][29]. This workflow also adapted an upgraded variant-calling method to rate and report cancer-related DNA mutations called from RNA-sequencing (RNAseq) data [30,31].…”

Section: Introductionmentioning

confidence: 99%

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Blood-based Genomic and Cellular Determinants of Response to Neoadjuvant PD-1 Blockade in Patients with Non-Small-Cell Lung Cancer

Zhang

Chen

et al. 2021

Preprint

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Background: For patients with non-small cell lung cancer (NSCLC), the PD-1/PD-L1 blockade treatment were incorporated into first-line treatment commonly. Despite the improved survival observed in PD-1 blockade treatment, a large proportion of patients do not respond while others actually progress during treatment. Method: Transcriptomic profiling was performed on whole blood samples from 30 patients received anti-PD-1 (Tislelizumab) plus chemotherapy. Expression levels of differentially expressed genes (DEGs) identified from two comparisons (post-and pre-treatment, responders and non-responders) were validated by real-time quantitative PCR, analyzed within tissue database and meta-analysis database, then followed by enrichment analysis in high-level representations and in silico leukocyte deconvolution. Results: A panel of blood-based gene signatures (FDR p<0.05, fold change<-2 or >2) were identified (DEG n=155 and 112 in two comparisons) and validated that not only differentially expressed between post- and pre- treatment or responders and non-responders but also in tissue samples between normal and tumor. Genes DLG5 and H3C10 were found negatively associated with overall survival (p<0.05). Enrichment of immunological and metabolism pathways and gene sets indicating activated circulating leukocytes were observed. Conclusion: The molecular and cellular signatures characterized in this study may provide potential blood-based predictors of the response to PD-1 blockade treatment in NSCLC patients.

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“…CFTR dysfunction in CF humans and mice is found to actively select the gut microbiome [25][26][27][28][29] , and causes heightened inflammation with increased numbers of inflammatory cells in the intestines 30,31 . Furthermore, extensive research demonstrates that CFTR loss-of-function in immune cells, including neutrophils 32,33 , monocytes 34,35 , and macrophages 36 , compromises their immune functions 34,[36][37][38][39][40][41][42] . Despite these functional impairments, it is not determined whether the CF immune defect is directly involved in shaping the intestinal microbiota.…”

mentioning

confidence: 99%

Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota

et al. 2022

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Cystic fibrosis (CF) is a life-threatening genetic disorder, caused by mutations in the CF transmembrane-conductance regulator gene (cftr) that encodes CFTR, a cAMP-activated chloride and bicarbonate channel. Clinically, CF lung disease dominates the adult patient population. However, its gastrointestinal illness claims the early morbidity and mortality, manifesting as intestinal dysbiosis, inflammation and obstruction. As CF is widely accepted as a disease of epithelial dysfunction, it is unknown whether CFTR loss-of-function in immune cells contributes to these clinical outcomes. Using cftr genetic knockout and bone marrow transplantation mouse models, we performed 16S rRNA gene sequencing of the intestinal microbes. Here we show that cftr deletion in both epithelial and immune cells collectively influence the intestinal microbiota. However, the immune defect is a major factor determining the dysbiosis in the small intestine, while the epithelial defect largely influences that in the large intestine. This finding revises the current concept by suggesting that CF epithelial defect and immune defect play differential roles in CF intestinal disease.

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CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons

Cited by 9 publications

References 82 publications

A Compensatory RNase E Variation Increases Iron Piracy and Virulence in Multidrug-ResistantPseudomonas aeruginosaduring Macrophage Infection

A Compensatory RNase E Variation Increases Iron Piracy and Virulence in Multidrug-ResistantPseudomonas aeruginosaduring Macrophage Infection

Blood-based Genomic and Cellular Determinants of Response to Neoadjuvant PD-1 Blockade in Patients with Non-Small-Cell Lung Cancer

Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota

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