Author
Eteri Bakhsoliani
Other affiliations: Imperial College London, Medical Research Council
Bio: Eteri Bakhsoliani is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Rhinovirus & Asthma. The author has an hindex of 10, co-authored 18 publications receiving 953 citations. Previous affiliations of Eteri Bakhsoliani include Imperial College London & Medical Research Council.
Topics: Rhinovirus, Asthma, COPD, Exacerbation, Innate lymphoid cell
Papers
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TL;DR: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo and relate to exacerbation severity, which is a novel therapeutic approach for asthma exacerbations.
Abstract: Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays ...
473 citations
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TL;DR: Rinovirus induction of type I interferon protein was delayed and deficient in BAL cells from asthmatic patients, and lower interferons levels were associated with greater airway hyperresponsiveness and skin prick test response positivity.
Abstract: Background Asthmatic patients have defective rhinovirus-induced IFN-β and IFN-λ production from bronchial epithelial cells and IFN-λ from bronchoalveolar lavage (BAL) cells. Whether bronchoalveolar lavage cells have defective type I interferon responses to rhinovirus is unknown, as are mechanisms explaining defective rhinovirus interferon induction in asthmatic patients. Objective We sought to investigate rhinovirus induction of type I interferons in BAL and blood mononuclear cells from asthmatic patients and healthy subjects and to investigate mechanisms of any deficiency observed. Methods BAL and blood mononuclear cells from atopic asthmatic patients and healthy subjects were infected with rhinovirus ex vivo . Interferon proteins were analyzed by using ELISA. mRNA expression of key components of interferon induction pathways were analyzed by using quantitative PCR. Results Rhinovirus induction of type I interferon protein was delayed and deficient in BAL cells from asthmatic patients, and lower interferon levels were associated with greater airway hyperresponsiveness and skin prick test response positivity. Expression of Toll-like receptor (TLR) 3, TLR7, TLR8, retinoic acid–inducible gene I (RIG-I), melanoma differentiation–associated gene 5 (MDA-5), TIR domain–containing adapter-inducing IFN-β (TRIF), myeloid differentiation primary response gene 88 (MyD88), caspase recruitment domain adaptor inducing IFN-β (CARDIF), IL-1 receptor–associated kinase 4 (IRAK4), IκB kinase β (IKKB), IκB kinase ι (IKKI), interferon regulatory factors 3 and 7, and rhinovirus induction of expression of the virus-inducible molecules TLR3, TLR7, RIG-I, and MDA-5 were not impaired in these interferon-deficient BAL cells in asthmatic patients. Defective rhinovirus interferon induction was not observed in blood mononuclear cells. Conclusions Rhinovirus induction of type I interferons in BAL cells is delayed and deficient and might be a marker of more severe asthma. Defective rhinovirus interferon induction in asthmatic patients was not accompanied by differences in the expression or induction of key molecules implicated in viral induction of interferons.
173 citations
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TL;DR: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation.
96 citations
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TL;DR: Hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma are an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21.
85 citations
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TL;DR: It is shown that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice, and a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD.
Abstract: Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp−/−) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
69 citations
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TL;DR: How prenatal and postnatal factors shape the development of both the microbiome and the immune system are described and the prospects of microbiome-mediated therapeutics and the need for more effective approaches that can reconfigure bacterial communities from pathogenic to homeostatic configurations are discussed.
Abstract: Recent studies have characterized how host genetics, prenatal environment and delivery mode can shape the newborn microbiome at birth. Following this, postnatal factors, such as antibiotic treatment, diet or environmental exposure, further modulate the development of the infant's microbiome and immune system, and exposure to a variety of microbial organisms during early life has long been hypothesized to exert a protective effect in the newborn. Furthermore, epidemiological studies have shown that factors that alter bacterial communities in infants during childhood increase the risk for several diseases, highlighting the importance of understanding early-life microbiome composition. In this review, we describe how prenatal and postnatal factors shape the development of both the microbiome and the immune system. We also discuss the prospects of microbiome-mediated therapeutics and the need for more effective approaches that can reconfigure bacterial communities from pathogenic to homeostatic configurations.
766 citations
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University of Oxford1, Wellington Management Company2, University of Barcelona3, University of Melbourne4, University of Amsterdam5, Ghent University Hospital6, Erasmus University Rotterdam7, National Institutes of Health8, Imperial College London9, Université de Montréal10, University of California, San Francisco11, Boston Children's Hospital12, University of Newcastle13, John Hunter Hospital14, Queen's University Belfast15, University of Western Australia16, Université Paris-Saclay17, French Institute of Health and Medical Research18, University of New South Wales19, University of Arizona20, Ludwig Maximilian University of Munich21, University of Pittsburgh22, University of Cape Town23
TL;DR: The only way to make progress in the future is to be much more clear about the meaning of the labels used for asthma and to acknowledge the assumptions associated with them, which are believed to be the most important causes of the stagnation in key clinical outcomes observed in the past 10 years.
712 citations
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TL;DR: The nasopharynx is a reservoir for microbes associated with acute respiratory infections (ARIs) and targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.
682 citations
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TL;DR: 15 years of discoveries on IL‐33 protein are highlighted, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases.
Abstract: Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8+ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
504 citations
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TL;DR: The cytokine networks driving asthma are reviewed, placing these in cellular context and incorporating insights from cytokine-targeting therapies in the clinic, to argue that the development of new and improved therapeutics will require understanding the diverse mechanisms underlying the spectrum of asthma pathologies.
501 citations