Biology subjects

White, M. P.

Publications and source records attributed to White, M. P..

6 recordsLinked to original sources

bioRxiv2025

IL-13 Modulates Antiviral Effector and Proinflammatory Pathways in Rhinovirus-Infected Pediatric Bronchial Epithelium

BackgroundRhinovirus (RV) is the most common trigger of viral-induced pediatric asthma exacerbations. The impact of IL-13-driven inflammation, common in pediatric asthma, on airway epithelial antiviral and inflammatory responses to RV remain unclear. ObjectiveDetermine how IL-13-driven T2 inflammation modulates pediatric bronchial epithelial cell responses to RV infection. MethodsBronchial epithelial cells (BECs) were collected from children with (n=50) and without (n=11) asthma. They were differentiated at an air-liquid interface for 21 days, pretreated with IL13 (10ng/mL) for 7 days to model T2 inflammation, then infected with RV-A16 (MOI 0.5). RNA sequencing of BECs was performed prior to and on days 2, 4, 7, and 10 post infection. Linear and generalized additive models partnered with pathway analysis identified differentially expressed gene clusters. ResultsRV infection, IL-13 stimulation, and their interaction each induced differentially expressed genes (7,808; 10,251; and 7,095 genes, respectively; FDR<0.05). IL-13 pretreatment did not alter RV load or a cluster enriched for interferon response and regulation genes, including IFNB1, IFNL1-3, STAT1/2, and CXCL10/11. In contrast, IL-13 reduced expression of distinct antiviral effectors (e.g. MX1/2, RSAD2, IFITM1-3; FDR=1.85x10-) and increased a secondary proinflammatory response cluster enriched for IL-15, TNF, ER stress, and cell-death pathways (FDR=3.63x10-). These clusters correlated with viral load in RV-infected cells, but IL13 pretreatment eliminated those associations. ConclusionsIL-13 does not modify viral load or interferon induction but selectively suppresses epithelial antiviral effector programs and enhances secondary inflammatory pathways during RV infection. These findings provide mechanistic insight into how T2 inflammation contributes to viral-triggered asthma morbidity. Key Messages- IL-13 did not alter rhinovirus viral load or epithelial interferon induction but selectively suppressed antiviral effector programs. This indicates that T2 inflammation reshapes antiviral defenses downstream of interferon signaling rather than impairing interferon production itself. - IL-13 enhances a distinct secondary proinflammatory cluster enriched for IL-15, TNF signaling, ER stress, and cell-death pathways. These late-phase responses may contribute to the heightened airway inflammation and injury observed during viraltriggered exacerbations in T2-high pediatric asthma. - IL-13-driven changes decouple epithelial immune responses from viral load, revealing mechanisms that may persist even with anti-IL-4R/IL-13 therapy. These findings identify epithelial antiviral effector pathways and IL-15/TNF-associated inflammatory programs as potential therapeutic targets for patients who experience breakthrough viral exacerbations despite IL-13 blockade. Capsule SummaryIL-13 did not alter rhinovirus load or epithelial interferon but selectively suppressed antiviral effectors and amplified secondary inflammatory pathways, revealing how T2-inflammation may worsen viral-triggered asthma exacerbations and contribute to breakthrough exacerbations despite IL-4R/IL-13-targeted therapy.

cell biology↗

bioRxiv2025

Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma

Host factors influencing susceptibility to rhinovirus-induced asthma exacerbations remain poorly characterized. Using organotypic bronchial epithelial cultures from well-characterized children with asthma and healthy children, this study investigated viral load kinetics and resultant host responses by bulk and single-cell transcriptomics and targeted protein analyses. Bronchial epithelium from exacerbation-prone children exhibited greater rhinovirus replication and a cascade of exaggerated downstream interferon (IFN), inflammatory, epithelial stress, and remodeling responses. These transcriptional patterns were confirmed and further refined using single-cell transcriptomics, revealing cell type-specific contributions--particularly from non-ciliated cell populations including secretory immune response, tuft, and basal cells. We observed that these post-infection differences were associated with lower pre-infection IFN-stimulated gene (ISG) expression and protein levels of the ISG CXCL10. Prophylactic IFN-{beta} treatment reduced viral replication and normalized downstream responses, supporting low baseline (pre-infection) IFN tone as a modifiable causal determinant of host susceptibility to adverse rhinovirus-induced responses in exacerbation-prone children with asthma.

cell biology↗

bioRxiv2025

Viral replication and interferon responses in bronchial epithelia is enhanced by Th17 cells

RationaleThe impact of Th17 lymphocytes on epithelial responses to rhinovirus infection in asthma is poorly characterized. MethodsBronchial epithelial cells (BECs) from children with asthma were differentiated to an organotypic epithelium and primed via co-culture with healthy donor Th17 lymphocytes for 4 days prior to apical infection with human rhinovirus-16 (RV-16). RNA sequencing with WGCNA analysis was performed to identify modules of gene expression altered by Th17 priming or RV-16 infection in BECs or Th17 cells. Gene expression was correlated with viral copy number and with secreted protein levels. ResultsAnalysis identified 4,030 genes grouped into 9 named modules with differential gene expression in BECs due to Th17 priming and viral infection. Modules with increased expression with Th17 priming and RV-16 infection included Interferon, MAP-kinase and TNF Signaling modules, while expression of Cilia structure/function and Metabolism modules were decreased. Th17 cells co-cultured with RV-16 infected BECs exhibited increased expression of an Interferon and Viral Response Module without detectable direct viral infection of Th17 cells.Increased expression of the Interferon Signaling in BECs and Interferon Response in Th17 cells was correlated with increased viral copy number in BECs. Th17 priming of BECs led to increased secretion of IFN-, IFN-{gamma}, and IL-1{beta} following RV-16 as compared to BECs alone. ConclusionsTh17 lymphocytes enhance epithelial interferon responses to RV-16 infection in bronchial epithelium from asthmatic children.

cell biology↗

bioRxiv2024

Nature exposure induces hypoalgesia by acting on nociception-related neural processing

Nature exposure has numerous psychological benefits, and previous findings suggest that exposure to nature reduces self-reported acute pain. Given the multi-faceted and subjective quality of pain and methodological limitations of prior research, it is unclear whether the evidence indicates genuine hypoalgesia or results from domain-general effects and subjective reporting biases. This preregistered functional neuroimaging study aimed to identify how nature exposure modulates nociception-related and domain-general brain responses to acute pain. We compared the self-reported and neural responses of healthy neurotypical participants (N = 49) receiving painful electrical shocks while exposed to virtual nature or to closely matched urban and indoor control settings. Replicating existing behavioral evidence, pain was reported to be lower during exposure to the natural compared to the urban or indoor control settings. Crucially, machine-learning-based multi-voxel signatures of pain demonstrated that this subjective hypoalgesia was associated with reductions in nociception-related rather than domain-general cognitive-emotional neural pain processing. Preregistered region-of-interest analyses corroborated these results, highlighting reduced activation of areas connected to lower-level somatosensory aspects of pain processing (such as the thalamus, secondary somatosensory cortex, and posterior insula). These findings demonstrate that nature exposure results in genuine hypoalgesia and that neural changes in lower-level nociceptive pain processing predominantly underpin this effect. This advances our understanding of how nature may be used as a non-pharmacological pain treatment. That this hypoalgesia was achieved with brief and easy-to-administer virtual nature exposure has important practical implications and opens novel avenues for research on the precise mechanisms by which nature impacts our mind and brain.

neuroscience↗

bioRxiv2021

Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

IntroductionCommon alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses. MethodsIn airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-{beta} or IFN-{lambda}, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6-18 yrs.) and older adults (ages 60-75 yrs.) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 hrs. following infection and supernatant was collected 48 and 96 hrs. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-{beta}1 or IFN-{lambda}2 before SARS-CoV-2 infection. ResultsDespite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFN{beta}1 or IFN{lambda}2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication. DiscussionIn addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-{beta}1 or IFN-{lambda}2, markedly reduces SARS-CoV-2 replication.

immunology↗

bioRxiv2020

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. Additionally, Th2 polarization digresses in the absence of CCT-controlled protein folding resulting paradoxically in continued IFN-{gamma} expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.

immunology↗