STAT3 mutation-associated airway epithelial defects in Job syndrome

Zhang, Yihan; Tian, Lin; Leung, Hui Min; Zhang, Cheng; Wilson-Mifsud, Brittany; Feldman, Michael B.; Puel, Anne; Couderc, Louis‐Jean; Danion, François; Catherinot, Émilie; Salvator, Hélène; Tcherkian, Colas; Givel, C.; Xu, Jie; Tearney, Guillermo J.; Vyas, Jatin M.; Li, Hu; Hurley, Bryan P.; Mou, Hongmei

doi:10.1016/j.jaci.2022.12.821

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…The dose of Stattic (20 µM) was determined based on its efficacy in blocking the increase in p-STAT3 Y 705 levels in response to IL6 (Figure S8A). Of note, Stattic treatment had no effect on the expression of a RSV receptor known to be expressed by ciliated cells, IGF1R 54 (Figure S8B) or barrier function of well-differentiated epithelial cells in adult ALI cultures 55 . At 2 dpi, Stattic treatment doubled the number of RSV-infected cells and the viral RNA level compared to solvent control (Figures 6B-6D).…”

Section: Resultsmentioning

confidence: 98%

“…In a second approach, we employed a doxycycline (Dox)-inducible shRNA system to knockdown STAT3. Dox was administered from day 18 in ALI (Figures 6E and 6F), when multiple epithelial cell types are already generated 37,38 , to minimize the effect of STAT3 inhibition on ciliated cell differentiation 55,56 . STAT3 knockdown in adult ALI cultures resulted in almost 3 times more RSV-infected cells and induced apoptosis in ∼60% of RSV-infected cells (Figures 6G and 6H).…”

Section: Resultsmentioning

confidence: 99%

“…STAT3 knockdown in adult ALI cultures resulted in almost 3 times more RSV-infected cells and induced apoptosis in ∼60% of RSV-infected cells (Figures 6G and 6H). In the third approach, we isolated bronchial BSCs from lung biopsy samples from healthy adult donors and an adult patient with Job syndrome harboring a hypomorphic STAT3-S560del mutation 55 (Figure S9A). As previously reported 55 , STAT3-S560del BSCs had a reduced capacity to differentiate into ciliated cells compared to healthy biopsy BSCs (Figures S9B and S9C).…”

Section: Resultsmentioning

confidence: 99%

“…BSCs of one patient with Job syndrome were isolated from fresh discarded surgical specimens under an approved IRB protocol (No. 2017P001479) 55 and expanded similarly as TA BSCs.…”

Section: Bsc Isolation and Expansionmentioning

confidence: 99%

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Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelial cells

Zhao,

Wang,

Bai

et al. 2023

Preprint

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Respiratory syncytial virus (RSV) can cause severe disease especially in infants; however, mechanisms of age-associated disease severity remain elusive. Here, employing human bronchial epithelium models generated from tracheal aspirate-derived basal stem cells of neonates and adults, we investigated whether age regulates RSV epithelium interaction to determine disease severity. We show that following RSV infection, only neonatal epithelium model exhibited cytopathy and mucus hyperplasia, and neonatal epithelium had more robust viral spread and inflammatory responses than adult epithelium. Mechanistically, RSV-infected neonatal ciliated cells displayed age-related impairment of STAT3 activation, rendering susceptibility to apoptosis, which facilitated viral spread. In contrast, SARS-CoV-2 infection of ciliated cells had no effect on STAT3 activation and was not affected by age. Taken together, our findings identify an age-related and RSV-specific interaction with neonatal bronchial epithelium that critically contributes to severity of infection, and STAT3 activation offers a potential strategy to battle severe RSV disease in infants.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…BSCs of one patient with Job syndrome were isolated from fresh discarded surgical specimens under an approved IRB protocol (No. 2017P001479) 55 and expanded similarly as TA BSCs.…”

Section: Bsc Isolation and Expansionmentioning

confidence: 99%

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Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelial cells

Zhao,

Wang,

Bai

et al. 2023

Preprint

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“…STAT3 is ubiquitously expressed and multisystemic features are present. Thus, deficient epithelial STAT3 signaling may contribute to aberrant staphylococcal control by cytokine dysregulation and aberrant tissue remodeling ( 54 , 55 ). STAT3 is involved in both pro- and anti-inflammatory signaling which complicates our understanding of single factors for the overall phenotype.…”

Section: Introductionmentioning

confidence: 99%

Inborn errors of immunity with susceptibility to S. aureus infections

Kurz,

Lehmberg,

Farmand

2024

Front. Pediatr.

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Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

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The pulmonary effects of STAT3 deficiency

Gilje¹,

Abbott²

2023

Journal of Allergy and Clinical Immunology

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STAT3 mutation-associated airway epithelial defects in Job syndrome

Cited by 8 publications

References 49 publications

Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelial cells

Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelial cells

Inborn errors of immunity with susceptibility to S. aureus infections

The pulmonary effects of STAT3 deficiency

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