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Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H2O2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H2O2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H2O2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.

PurposeEnhanced understanding of the dynamic changes in the dysregulated inflammatory response in COVID-19 may help improve patient selection and timing for immunomodulatory therapies.MethodsWe enrolled 323 COVID-19 inpatients on different levels of baseline respiratory support: i) Low Flow Oxygen (37%), ii) Non-Invasive Ventilation or High Flow Oxygen (NIV_HFO, 29%), iii) Invasive Mechanical Ventilation (IMV, 27%), and iv) Extracorporeal Membrane Oxygenation (ECMO, 7%). We collected plasma samples upon enrollment and days 5 and 10 to measure host-response biomarkers. We classified subjects into inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker and subphenotype trajectories and outcomes during hospitalization.ResultsIL-6, procalcitonin, and Angiopoietin-2 were persistently elevated in patients at higher levels of respiratory support, whereas sRAGE displayed the inverse pattern. Patients on NIV_HFO at baseline had the most dynamic clinical trajectory, with 26% eventually requiring intubation and exhibiting worse 60-day mortality than IMV patients at baseline (67% vs. 35%, pConclusionsLongitudinal study of systemic host responses in COVID-19 revealed substantial and predictive inter-individual variability, influenced by baseline levels of respiratory support and concurrent immunomodulatory therapies.

Rationale: There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to coronavirus disease (COVID-19). Objectives: To compare key demographic and physiologic parameters, biomarkers, and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia. Methods: We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study and compared them with a historical, pre–COVID-19 cohort of patients with viral ARDS (n = 14), bacterial ARDS (n = 21), and ARDS due to culture-negative pneumonia (n = 30). We recorded clinical demographics; measured respiratory mechanical parameters; collected serial peripheral blood specimens for measurement of plasma interleukin (IL)-6, IL-8, and IL-10; and followed patients prospectively for patient-centered outcomes. We conducted between-group comparisons with nonparametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models. Results: Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared with those with non–COVID-19 ARDS (P < 0.05). Patients with COVID-19 had lower delivered minute ventilation compared with bacterial and culture-negative ARDS (post hoc P < 0.01) but not compared with viral ARDS. We found no differences in static compliance, hypoxemic indices, or carbon dioxide clearance between groups. Patients with COVID-19 had lower IL-6 levels compared with bacterial and culture-negative ARDS at early time points after intubation but no differences in IL-6 levels compared with viral ARDS. Patients with COVID-19 had longer duration of mechanical ventilation but similar 60-day mortality in both unadjusted and adjusted analyses. Conclusions: COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared with bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared with non–COVID-19 ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.

Rationale: Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement a...

The present study briefs the structural and optical properties of Gd doped BaZr0.05Ti0.95O3 ceramic synthesized via solid-state reaction (SSR) technique. The X-Ray diffraction (XRD) study reveals t...

Plasma SARS-CoV-2 viral RNA (vRNA) levels are predictive of COVID-19 outcomes in hospitalized patients, but whether plasma vRNA reflects lower respiratory tract (LRT) vRNA levels is unclear. We compared plasma and LRT vRNA levels in serially collected samples from mechanically ventilated patients with COVID-19. LRT and plasma vRNA levels were strongly correlated at first sampling (n = 33, r = 0.83, P < 10−9) and then declined in parallel in available serial samples except in nonsurvivors who exhibited delayed vRNA clearance in LRT samples. Plasma vRNA measurement may offer a practical surrogate of LRT vRNA burden in critically ill patients, especially early after ICU admission.

Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes.Prospective, observational cohort study.Medical ICU at a tertiary academic medical center.Mechanically ventilated patients with acute respiratory distress syndrome or ARFA.None.We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation.Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, predictors of outcomes within severe COVID-19 remain to be comprehensively elucidated. Recently, we identified divergent monocyte states as predictors of outcomes within severe COVID-19, but corresponding humoral profiles of risk have not been delineated. Furthermore, the nature of antibodies (Abs) directed against viral antigens beyond the spike protein or endemic coronavirus antigens and their associations with disease severity and outcomes remain poorly defined. We performed deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients admitted to the ICU. The profiles consisted of canonical (S, RBD, N) and non-canonical (orf3a, orf8, nsp3, nps13 and M) antigenic specificities. Notably, multivariate machine learning (ML) models, generated using profiles of Abs directed against canonical or non-canonical antigens, were equally discriminative of recovery and mortality COVID-19 outcomes. In both ML models, survivors were associated with increased virus-specific IgA and IgG3 antibodies and with higher antigen-specific antibody galactosylation. Intriguingly, pre-pandemic healthy controls had cross-reactive Abs directed against nsp13 which is a conserved protein in other alpha and beta coronaviruses. Notably, higher levels of nsp13-specific IgA antibodies were associated with recovery in severe COVID-19. In keeping with these findings, a model built on Ab profiles for endemic coronavirus antigens was also predictive of COVID-19 outcome bifurcation, with higher levels of IgA and IgG3 antibodies against OC43 S and NL63 S being associated with survival. Our results suggest the importance of Abs targeting non-canonical SARS-CoV-2 antigens as well as those directed against endemic coronaviruses in favorable outcomes of severe COVID-19.

A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.

Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H

Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar–capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar–capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic Mpl−/− mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary Pseudomonas aeruginosa (PA) infection; barrier disruption was attenuated by platelet reconstitution. Although PA infection was associated with a brisk neutrophil influx, depletion of airspace neutrophils failed to substantially mitigate PA-triggered alveolar barrier disruption in Mpl−/− mice. Rather, PA cell-free supernatant was sufficient to induce lung epithelial cell apoptosis in vitro and in vivo and alveolar barrier disruption in both platelet-depleted mice and Mpl−/− mice in vivo. Cell-free supernatant from PA with genetic deletion of the type 2 secretion system, but not the type 3 secretion system, mitigated lung epithelial cell death in vitro and lung injury in Mpl−/− mice. Moreover, platelet releasates reduced poly (ADP ribose) polymerase cleavage and lung injury in Mpl−/− mice, and boiling of platelet releasates, but not apyrase treatment, abrogated PA supernatant–induced lung epithelial cell cytotoxicity in vitro. These findings indicate that while neutrophil airspace influx does not potentiate infectious lung injury in the thrombocytopenic host, platelets and their factors protect against severe pulmonary complications from pathogen-secreted virulence factors that promote host cell death even in the absence of overt infection.

We study the geomagnetic activity Ap-index in relation to sunspot number and area for the interval covering Solar Cycles 17 to 24 (1932 – 2019), in view of the availability of data for the Ap-index from 1932 on, in order to predict the amplitude of Sunspot Cycle 25. We examine the statistical relationship between sunspot-maximum amplitude and Ap-index, and similarly that between sunspot area and Ap-index. We apply the $\chi ^{2}$ -test for the best fit between two parameters and obtain the correlation coefficient. We also derive the standard deviation for the error limits in the predicted results. Our study reveals that the amplitude of the Sunspot Cycle 25 is likely to be $\approx 100.21 \pm 15.06$ and it may peak in April $2025\pm 6.5$ months. On the other hand, the sunspot area will have maximum amplitude $\approx 1110.62 \pm 186.87$ μ Hem and may peak in February $2025\pm 5.8$ months, which implies that Solar Cycle 25 will be weaker than or comparable to Solar Cycle 24. In view of our results as well as those of other investigators, we propose that the Sun is perhaps approaching a global minimum.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations1, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality2,3. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

SUMMARY Bacterial pneumonia is a global healthcare burden, and unwarranted inflammation is suggested as an important cause of mortality. Optimum levels of the anti-inflammatory cytokine IL-10 are essential to reduce inflammation and improve survival in pneumonia. Elevated levels of the mitochondrial-DAMP cardiolipin (CL), reported in tracheal aspirates of pneumonia patients, have been shown to block IL-10 production from lung MDSCs. Although CL-mediated K107 SUMOylation of PPARγ has been suggested to impair this IL-10 production, the mechanism remains elusive. We identify PIAS2 to be the specific E3-SUMOligase responsible for this SUMOylation. Moreover, we identify a concomitant CL-mediated PPARγ S112 phosphorylation, mediated by JNK-MAPK, to be essential for PIAS2 recruitment. Furthermore, using a clinically tested peptide inhibitor targeting JNK-MAPK, we blocked these post-translational modifications (PTMs) of PPARγ and rescued IL-10 expression, improving survival in murine pneumonia models. Thus, we explore the mechanism of mito-DAMP-mediated impaired lung inflammation resolution and propose a therapeutic strategy targeting PPARγ PTMs., Graphical Abstract, In Brief Garg et al. identify the role of post-translational modifications of PPARγ in causing cardiolipin-mediated IL-10 suppression from lung myeloid-derived suppressor cells, thus increasing pneumonia severity. They identify multiple targets to reverse this suppression and improve IL-10 expression and lung inflammation resolution in bacterial pneumonia.

Summary Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular autophagic machinery, and knockdown of LC3B ablated virus production. RSV subverted LC3B with evidence of co-localization and caused a significant reduction in autophagic flux, both reversed by IL-22 treatment. Our findings inform a previously unrecognized anti-viral effect of IL-22 that can be harnessed to prevent RSV-induced severe respiratory disease., Graphical Abstract, Highlights • RSV infection of lung epithelial cells subverts the cellular autophagic machinery • RSV infection inhibits autophagic flux in infected cells • IL-22 inhibits RSV production from human lung epithelial cells and in neonatal mice • IL-22 blocks RSV-LC3B co-localization and restores cellular autophagic flux, Immunology; Virology; Cell Biology

SUMMARY Clinical definitions of asthma fail to capture the heterogeneity of immune dysfunction in severe, treatment-refractory disease. Applying mass cytometry and machine learning to bronchoalveolar lavage (BAL) cells, we find that corticosteroid-resistant asthma patients cluster largely into two groups: one enriched in interleukin (IL)-4+ innate immune cells and another dominated by interferon (IFN)-γ+ T cells, including tissue-resident memory cells. In contrast, BAL cells of a healthier population are enriched in IL-10+ macrophages. To better understand cellular mediators of severe asthma, we developed the Immune Cell Linkage through Exploratory Matrices (ICLite) algorithm to perform deconvolution of bulk RNA sequencing of mixed-cell populations. Signatures of mitosis and IL-7 signaling in CD206−FcεRI+CD127+IL-4+ innate cells in one patient group, contrasting with adaptive immune response in T cells in the other, are preserved across technologies. Transcriptional signatures uncovered by ICLite identify T-cell-high and T-cell-poor severe asthma patients in an independent cohort, suggesting broad applicability of our findings., Graphical abstract, In brief Asthma is an immune-mediated heterogeneous disease. Current type-2 biomarkers provide limited understanding of underlying pathobiology or therapeutic guidance. Using a multi-omics approach, Camiolo et al. identify two clusters of severe asthma patients with similar type-2 biomarkers but with strikingly distinct immune profiles and associated biological pathways.

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red blood cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulated findings observed with wildtype strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulates the STAT1 pathway with implications in severe infection.

BACKGROUND: Many severe asthma (SA) patients fail to respond to Type 2 inflammation targeted therapies. We previously identified a cohort of SA subjects expressing Type 1 inflammation manifesting with IFN-γ expression with variable Type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors CXCR3 and CCR5 in establishing Type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program (SARP I/II) were analyzed for pathway expression and paired with clinical parameters. Wild Type, Cxcr3(−/−) and Ccr5(−/−) mice were exposed to a Type 1(High) SA model with analysis of whole lung gene expression and histology. Wild type and Cxcr3(−/−) mice were treated with an FDA-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression correlated with CXCR3 and CCR5 expression but in Cxcr3(−/−) and Ccr5(−/−) mice Type 1 inflammation was preserved in a murine SA model, most likely due to compensation by the other pathway. Incorporation of maraviroc in the experimental model blunted airway hyperreactivity, despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. While these pathways provide redundancy for establishing Type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in Type 1(high) asthmatic individuals. CLINICAL IMPLICATIONS: In Type 1 high asthma, CCR5 and CXCR3 provide redundant pathways for lung inflammation, but CCR5 inhibition provides a potential novel target for reducing airway hyperreactivity.

Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients without ARDS, including downregulation of SOCS3 expression, accompanied by a proinflammatory signature with upregulation of multiple type I IFN–induced genes, especially in CD16(+) cells. To generate an ARDS risk score, we identified upregulation of 29 genes in the monocytes of these patients, and 17 showed a similar profile in cells of patients in independent cohorts. Monocytes had increased expression of RAB11A, known to inhibit neutrophil efferocytosis; ATP2B1, a calcium pump that exports Ca(2+) implicated in endothelial barrier disruption; and SPARC, associated with processing of procollagen to collagen. These data show that monocytes of ARDS patients upregulate expression of genes not just restricted to those associated with inflammation. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.

Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in critically ill Coronavirus disease 2019 (COVID-19) patients. Here, we present high-dimensional profiling of blood and respiratory samples in severe COVID-19 patients to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNAseq based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time leads to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2 infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral infected myeloid cells and protracted interferon signaling in severe COVID-19., Graphical Abstract, Cillo et al identify transcriptional profiles in peripheral blood that are associated with mortality in critically ill COVID-19 patients. Inflammatory monocyte signatures are correlated with CXCL10 in plasma and precede upregulation of inflammatory cytokines in blood. SARS-CoV-2-infected macrophages in the respiratory tract expressed CXCL10, linking peripheral and lung immune profiles.

SummaryInhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways.

A novel tapioca starch (TS)-based energy efficient natural sizing technology for sizing jute yarn was developed. The performance of the developed formulation was tested in a laboratory at pilot scale and subsequently validated through industrial-level shop floor trials vis-a-vis the conventional tamarind kernel powder (TKP)-based sizing. Unlike TKP sizing, the developed natural size paste formulation did not require “cooking” at elevated temperature, and could be maintained at room temperature in sow box. In addition, TS-based sized yarns could be dried at lower temperature. TS-sized jute yarns showed better abrasion resistance, and slightly better tensile strength values when compared with conventional TKP-sized yarns. TS-based sized jute yarns exhibited better elastic recovery compared with TKP-sized yarns under cyclic loading. The sizing effluents were found to be drastically reduced in TS-based recipe showing lower Biological Oxygen Demand and Chemical Oxygen Demand. Using TS-based sizing formulation,...

BACKGROUND Exposure to innocuous inhaled foreign antigens such as dust mite and pollen triggers aberrant immune responses in the respiratory tract of individuals genetically predisposed to asthma. Immune tolerance restricts such overreaction and plays a key role in preventing unwanted inflammatory responses. Yet the mechanisms underlying this protection are still largely unclear. Our studies of immune tolerance in regulation of experimental asthma and those of others in the context of cancer demonstrated PPARγ-facilitated fatty acid oxidation (FAO) resulting in mitochondrial H2O2 production in dendritic cells (DCs) in promotion of immune tolerance. However, neither study addressed whether mitochondrial H2O2 is essential for suppression of inflammation in response to antigens. OBJECTIVE In this study, we sought to establish a mouse model of airway tolerance to inhaled house dust mite (HDM) allergen in newborn mice and study the role of mitochondrial H2O2 in tolerance establishment. METHODS AND RESULTS Repeated exposure of wild type (WT) mice to a low dose of the common allergen HDM in early life suppressed airway inflammation and airway hyperreactivity when the mice were challenged by a high dose of the allergen in adulthood. This protective effect was abolished in MCAT transgenic mice, which overexpress the catalase gene in their mitochondria. The inflammatory phenotype in the MCAT mice was associated with a high TH2 response facilitated by lung dendritic cells (DCs). CONCLUSIONS Our study illustrates a crucial role of mitochondrial H2O2 in the establishment of airway tolerance in early life, which suppresses DC-mediated TH2 response.

OBJECTIVE To study the ability of the host protective cytokine interleukin-22 (IL-22) to block productive infection of airway epithelial cells by Respiratory Syncytial Virus (RSV). BACKGROUND RSV infection can cause severe bronchiolitis and pneumonia in infants. However, no vaccine against RSV is currently available. RSV primarily infects both proximal and distal airways as well as alveolar epithelial cells in the lungs. IL-22 has mucosal-protective effects, known to preserve epithelial-barrier functions and promote host defense against pathogens. We, therefore, initiated studies to determine whether IL-22 can control RSV infection of airway epithelial cells (AECs). METHODS Primary human AECs differentiated under air-liquid interface (ALI) culture conditions were used for RSV infection (multiplicity of infection (MOI) 2) and then treated with IL-22 (50 ng/ml). 5-day old newborn C57BL/6 mice were intranasally infected with 1×106 PFU of RSV and then treated with an IL-22-Fc fusion protein (5 μg/mouse) intraperitoneally on day 3 p.i. Confocal imaging approach was utilized to determine co-localization of RSV and LC3B and to differentiate between autophagosomes and autolysosomes. RESULTS Treatment with IL-22 led to a significant decrease in viral load in primary human AECs as well as in vivo in mouse lungs. Confocal imaging and other approaches revealed subversion of the autophagic machinery by RSV for its own production, which was significantly inhibited by IL-22, thereby preserving autophagy in a STAT3 dependent manner. CONCLUSIONS IL-22 inhibits RSV production in both primary human airway epithelial cells and mouse lungs by preserving cellular autophagy thereby blocking hijacking of the autophagic apparatus by RSV.

Background 5–10% of severe asthmatics are resistant to corticosteroids but account for 50% of health care costs spent on asthma care in the US and in Europe. 30–40% of corticosteroid-resistant severe asthmatic patients show elevated IFN-γ levels (Type1 immune response) in BAL cells that is closely associated with expression of CXCL10, a downstream IFN-γ target, and a marker of senescence associated secretory phenotype (SASP). Objective The goal of this study was to evaluate the role of SASP in severe asthma associated with an elevated level of corticosteroid-refractory IFN-γ in the airways. Methods Wild type BALB/c and IFN-γ−/− mice were sensitized with house dust mite (HDM) in combination with cdi-GMP and then subsequently repeatedly challenged with HDM. Lungs from these and control mice were subjected to either RNA-seq analysis or used for β-gal staining to demonstrate cellular senescence. Results Whole lungs from WT mice subjected to the severe asthma (SA) model demonstrated significantly higher expression of several SASP genes which included p16INK4a, CXCL10, MMP12 and IL-6 as compared to that detected in naïve WT mice. p16INK4a is a key regulator of premature cellular senescence that arrests cell cycle in G1 phase by inhibiting CDK4 and CDK6 and has been associated with corticosteroid resistance. Further, the SASP genes p16INK4a, CXCL10 and CCL8 were downregulated in the absence of IFN-γ suggesting a possible role of elevated IFN-γ in SASP induction. The lung sections from mice subjected to the SA model showed increased numbers of b-gal positive cells as compared to that found in control mice. Conclusion SASP may underlie persistent inflammation and corticosteroid resistance observed in a subset of severe asthma patients.