High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity

Allison Welham; Elizabeth Chorvinsky; Surajit Bhattacharya; Betelehem Solomon Bera; Kyle Salka; Jered Weinstock; Xilei Xu Chen; Geovanny F Perez; Dinesh K Pillai; Maria J Gutierrez; Hiroki Morizono; Jyoti Jaiswal; Gustavo Nino

doi:10.1111/imm.13741

High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity

Immunology. 2023 Dec 26. doi: 10.1111/imm.13741. Online ahead of print.

Authors

Allison Welham^{1

2}, Elizabeth Chorvinsky^{1

2}, Surajit Bhattacharya^{1

2}, Betelehem Solomon Bera^{1

2}, Kyle Salka^{1

2}, Jered Weinstock^{1

2}, Xilei Xu Chen³, Geovanny F Perez³, Dinesh K Pillai^{1

2}, Maria J Gutierrez⁴, Hiroki Morizono², Jyoti Jaiswal², Gustavo Nino^{1

2}

Affiliations

¹ Division of Pediatric Pulmonary and Sleep Medicine, Children's National Hospital, Washington, DC, USA.
² George Washington University, Washington, DC, USA.
³ Division of Pediatric Pulmonology, Oishei Children's Hospital, University at Buffalo, Buffalo, New York, USA.
⁴ Division of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA.

PMID: 38148520
DOI: 10.1111/imm.13741

Abstract

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1-24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as 'high TSLP' or 'low TSLP' for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long-term impact of viral respiratory illnesses during early infancy and beyond childhood.

Keywords: TSLP; airway; epithelium; paediatrics; viral bronchiolitis; virus.

Abstract

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