Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) has had a substantial positive impact for people living with cystic fibrosis (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment.

Long-Term PM Exposure and Upregulation of Expression in Nasal Epithelium from Youth with Asthma.

Background: Little is known about long-term PM exposure and airway epithelial gene expression.

Objective: To test for association between long-term PM exposure and nasal epithelial gene expression in youth with asthma.

Methods: Transcriptome-wide association study (TWAS) of long-term PM in nasal epithelium from youth aged 6-20 years in the: 1) Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR, n=182); 2) Vitamin D Kids Asthma Study (VDKA, n=58); and 3) Stress and Treatment Response in Puerto Rican and African American Children with Asthma study (STAR, n=81).

Sex-based differences in persistent lung inflammation following influenza infection of juvenile outbred mice.

Children are susceptible to influenza infections and can experience severe disease presentation due to a lack of or limited pre-existing immunity. Despite the disproportionate impact influenza has on this population, there is a lack of focus on pediatric influenza research, particularly when it comes to identifying the pathogenesis of long-term outcomes that persist beyond the point of viral clearance. In this study, juvenile outbred male and female mice were infected with influenza and analyzed following viral clearance to determine how sex impacts the persistent inflammatory responses to influenza.

Distinct roles for type I and type III interferons in virulent human metapneumovirus pathogenesis.

Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV.

PD-1 signaling in neonates restrains CD8 T cell function and protects against respiratory viral immunopathology.

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1).

Nasal epithelial gene expression and total IgE in children and adolescents with asthma.

Background: Little is known about nasal epithelial gene expression and total IgE in youth.

Objective: We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types.

Methods: We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma.

Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma.

Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity.

Cis- and trans-eQTM analysis reveals novel epigenetic and transcriptomic immune markers of atopic asthma in airway epithelium.

Background: Expression quantitative trait methylation (eQTM) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 megabase).

Objectives: This study sought to identify cis- and trans-methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma.

Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma.

Background: The mechanisms underlying the known link between overweight/obesity and childhood asthma are unclear. We aimed to identify differentially expressed genes and pathways associated with obesity-related asthma through a transcriptomic analysis of nasal airway epithelium.

Methods: We compared the whole transcriptome in nasal airway epithelium of youth with overweight or obesity and asthma with that of youth of normal weight and asthma, using RNA sequencing data from a cohort of 235 Puerto Ricans aged 9-20 years (EVA-PR) and an independent cohort of 66 children aged 6-16 years in Pittsburgh (VDKA).

Nitroalkene fatty acids modulate bile acid metabolism and lung function in obese asthma.

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma.

Testosterone-to-estradiol ratio and lung function in a prospective study of Puerto Rican youth.

Background: Age- and sex-related differences in asthma may be due to changes in sex hormone levels.

Objective: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth.

Methods: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico.

Insights Into Type I and III Interferons in Asthma and Exacerbations.

Asthma is a highly prevalent, chronic respiratory disease that impacts millions of people worldwide and causes thousands of deaths every year. Asthmatics display different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures, and are broadly characterized into type 2-high or type 2-low (non-type 2) endotypes by linking clinical characteristics, steroid responsiveness, and molecular pathways. Regardless of asthma severity and adequate disease management, patients may experience acute exacerbations of symptoms and a loss of disease control, often triggered by respiratory infections.

IL-22-binding protein exacerbates influenza, bacterial super-infection.

Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary pathogens of interest. IL-22 promotes S. aureus and S.

STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection.

Influenza is a common respiratory virus that infects between 5 and 20% of the US population and results in 30,000 deaths annually. A primary cause of influenza-associated death is secondary bacterial pneumonia. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type 17 immune responses, resulting in exacerbation of bacterial burden during influenza and super-infection.

STAT1 Is Required for Suppression of Type 17 Immunity during Influenza and Bacterial Superinfection.

Influenza is an annual, global health care concern. Secondary bacterial pneumonia is a severe complication associated with primary influenza virus infection, often resulting in critical morbidity and mortality. Our laboratory has identified influenza-induced suppression of anti-bacterial Type 17 immunity as a mechanism for enhanced susceptibility to bacterial super-infection.

Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease.

Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease.

The enigmatic role of IL-22 in asthma.

Asthma is a complex, heterogeneous disorder with increasing prevalence. It is now recognized that several asthma phenotypes exist, including type 2-high and type 2-low (or non-type 2) subsets. As current research strives to identify subgroups of asthmatics that share disease pathobiology to establish endotypes, efforts to clarify the underlying molecular mechanisms of disease are needed and essential.

A Novel CD4 T Cell-Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology.

Rationale: Infection with Pneumocystis, an opportunistic fungal pathogen, can result in fulminant pneumonia in the clinical setting of patients with immunosuppression. In murine models, Pneumocystis has previously been shown to induce a CD4 T cell-dependent eosinophilic response in the lung capable of providing protection.

Objectives: We sought to explore the role of Pneumocystis in generating asthma-like lung pathology, given the natural eosinophilic response to infection.

Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation.

IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs.

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1.

Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1.

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells.

Background: Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33.

A tale of two cytokines: IL-17 and IL-22 in asthma and infection.

The Th17 pathway has recently been shown to play a critical role in host defense, allergic responses and autoimmune inflammation. Th17 cells predominantly produce IL-17 and IL-22, which are two cytokines with broad effects in the lung and other tissues. This review summarizes not only what is currently known about the molecular regulation of this pathway and Th17-related cytokine signaling, but also the roles of these cytokines in pathogen immunity and asthma.

Clinical consequences of targeting IL-17 and TH17 in autoimmune and allergic disorders.

The TH17 lineage of T cells and its canonical cytokine IL-17 have been the focus of many recent studies in autoimmune, allergic, and infectious disease. In this review, we will briefly discuss the current knowledge about the role of these cells and IL-17 in a spectrum of disorders. It is clear that IL-17 plays pathogenic roles in certain conditions while the same pathway is critically important to immunity in others.

Leukocyte-derived extracellular superoxide dismutase does not contribute to airspace EC-SOD after interstitial pulmonary injury.

The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is known to limit inflammation and fibrosis following numerous pulmonary insults. Previous studies have reported a loss of full-length EC-SOD from the pulmonary parenchyma with accumulation of proteolyzed EC-SOD in the airspace after an interstitial lung injury. However, following airspace only inflammation, EC-SOD accumulates in the airspace without a loss from the interstitium, suggesting this antioxidant may be released from an extrapulmonary source.