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Airway epithelial hyperactivation of JAK-STAT signaling impairs type-III IFN responses during RSV infection in Down Syndrome [SingleCell RNA-seq]

ABSTRACT: Trisomy 21 (TS21) or Down syndrome (DS) causes a ninefold increase in the mortality risk in children from otherwise non-lethal respiratory syncytial virus (RSV) infection. However, it is not known if this lethality is due to increased viral infectivity, or downstream antiviral response. We analyzed the pediatric airway epithelial cells (AECs) - the primary point of viral entry and defense and found that the antiviral IFN-JAK/STAT signaling response is hyperactivated in T21 cells relative to euploid cells. This is associated with decreased RSV infection in TS21 AECs. Conversely, upon exposure to RSV, both the induction of IFN signaling and type-III IFN production are diminished in TS21 AECs and in patients in vivo. Treating TS21 AECs with JAK inhibitor alleviated the baseline type-III IFN upregulation without impairing their ability to activate IFN response upon viral exposure. This identifies a potential approach to mitigate the impact of RSV on children with DS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271139 | GEO | 2025/12/12

REPOSITORIES: GEO

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Project description:Rhinoviruses (RVs) are major instigators of acute exacerbations of asthma, COPD and other respiratory diseases. RVs are categorized into three species (RV-A, RV-B, and RV-C), which comprise more than 160 serotypes, making it difficult to develop an effective vaccine. Currently no effective treatment for RV infection is available. Pulmonary surfactant is an extracellular complex of lipids and proteins that plays a central role in regulating innate immunity in the lung. The minor pulmonary surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), are potent regulators of inflammatory processes, and exert antiviral activity against respiratory syncytial virus (RSV) and influenza A viruses (IAV). In the current study, we examined the potencies of POPG and PI against rhinovirus A16 (RV-A16) in primary human airway epithelial cells (AECs) differentiated at an air-liquid interface (ALI). After AECs were infected with RV-A16, PI reduced viral RNA copy number by 80% and downregulated (55-65%) expression of antiviral genes (MDA5, IRF7 and IFN-lambda). In contrast, POPG only slightly decreased MDA5 (24%) and IRF7 (11%) gene expression but did not inhibit IFN-lambda gene expression or RV-A16 replication in AECs. However, both POPG and PI inhibited (50-80%) IL6 and CXCL11 gene expression and protein secretion. PI treatment dramatically attenuated global gene expression changes induced by RV-A16 infection in AECs. Cell type enrichment analysis of viral regulated genes opposed by PI treatment revealed that PI inhibited viral induction of goblet cell metaplasia and virus-induced downregulation of ciliated, club, and ionocyte cell types. Notably, PI treament altered the ability of RV-A16 to regulate expression of some phosphatidylinositol 4-kinase (PI4K), acyl-CoA binding domain containing (ACBD) and low density lipoprotein receptor (LDLR) genes that play critical roles in the formation and functioning of replication organelles (ROs) required for RV replication in host cells. These data suggest PI can be used as a potent, non-toxic antiviral agent for RV infection prophylaxis and treatment.

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Airway epithelial hyperactivation of JAK-STAT signaling impairs type-III IFN responses during RSV infection in Down Syndrome [SingleCell RNA-seq]

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