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

ABSTRACT: Trisomy 21 (TS21), commonly known as Down syndrome (DS), increases mortality risk due to respiratory syncytial virus (RSV) in children by nearly 9-fold. Interferon (IFN)-mediated JAK/STAT antiviral signaling is altered in DS given that four IFN receptor genes reside on chromosome 21. This study unveils an interferonopathy in TS21 pediatric airway epithelial cells (AECs), the primary point of entry and defense against RSV. Relative to euploid cells, TS21 AECs show reduced RSV infection levels accompanied by baseline hyperactivation of IFNJAK/STAT antiviral signaling. Conversely, in response to RSV infection, both the induction of IFN signaling and type-III IFN production are reduced in TS21 AECs compared to controls. JAK inhibition mitigates baseline IFN hyperactivation and increases type-III IFN antiviral response in TS21 AECs. Our findings identify hyperactivation of IFN-JAK/STAT in AECs of children with DS as a potentially targetable mechanism for reducing the lethal impact of RSV infection in this vulnerable population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271245 | GEO | 2025/12/12

REPOSITORIES: GEO

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	GSE271245_TPMCounts_IFN.txt.gz	Txt

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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.

Project description:Maier2022 - Stochastic Dynamics of Type I Interferon Responses Our study aims to determine whether and how biochemical noise affects the information transduced in the JAK-STAT signaling pathway and investigate the transition between basal and activated state. To this end, we studied the stochastic responses of MxA and IFIT1 expression in Huh7.5 cells stimulated with IFN-$\alpha$. Using fluorescent reporters under the control of the authentic promoter/enhancer region of IFIT1 and MxA we collected data displaying the differences between expressing and non-expressing cells for the marker genes in a time-course experiment. We hypothesize that the JAK-STAT signaling pathway efficiently transmits information under stochastic environments. To test our working hypothesis, we developed a detailed mathematical model using the obtained time-resolved flow cytometry data to describe the elements in the JAK-STAT signaling pathway at single-cell resolution. This model allowed us to systematically test the influence of intrinsic and extrinsic noise in the IFN response. The developed model consists of 42 species and 62 reactions (reactions m1 to m62). To name the variables in the model we used the following conventions: 1) variables referring to mRNA are denoted by $m$ prefix. 2) Variables in phosphorylated use $p$ as prefix. 3) Gene promoters are represented by the gene's name in lowercase. 4) R1, R2, IR, AR and RC, represent the IFN receptor subunits, inactive, active and complex forms, respectively. 5) The compartment is superscripted to the species if the species exist in multiple compartments. A graphical representation of the interaction between variables in the model is given in Maier et. al 2022 (Fig. 1) and all reactions are listed in the Supplementary Information, Section S2.1. Note that we publish the SBML model without the observables (e.g. exp_IRF9_n) as the change in the number of particles is defined in relation to the starting value in the COPASI model which is not supported in SBML format. In order to reproduce the parameter estimation without any extra worj, we recommend the direct download of the provided copasi model linked in the article. This model is described in the article: Stochastic Dynamics of Type I Interferon Responses Benjamin D. Maier(*), Luis U. Aguilera(*), Sven Sahle, Pascal Mutz, Priyata Kalra, Christopher Dächert, Ralf Bartenschlager, Marco Binder, Ursula Kummer PLOS Computational Biology, 2022 (*) Equally contributing authors Abstract: Interferon (IFN) activates the transcription of several hundred of IFN stimulated genes (ISGs) that constitute a highly effective antiviral defense program. Cell-to-cell variability in the induction of ISGs is well documented, but its source and effects are not completely understood. The molecular mechanisms behind this heterogeneity have been related to randomness in molecular events taking place during the JAK-STAT signaling pathway. Here, we study the sources of variability in the induction of the IFN-alpha response by using MxA and IFIT1 activation as read-out. To this end, we integrate time-resolved flow cytometry data and stochastic modeling of the JAK-STAT signaling pathway. The complexity of the IFN response was matched by fitting probability distributions to time-course flow cytometry snapshots. Both, experimental data and simulations confirmed that the MxA and IFIT1 induction circuits generate graded responses rather than all-or-none responses. Subsequently, we quantify the size of the intrinsic variability at different steps in the pathway. We found that stochastic effects are transiently strong during the ligand-receptor activation steps and the formation of the ISGF3 complex, but negligible for the final induction of the studied ISGs. We conclude that the JAK-STAT signaling pathway is a robust biological circuit that efficiently transmits information under stochastic environments.

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

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