Respiratory Epithelial Cells Can Remember Infection: A Proof of Concept Study

2019 ◽  
Author(s):  
Jeanne Bigot ◽  
Loic Guillot ◽  
Juliette Guitard ◽  
Manon Ruffin ◽  
Harriet Corvol ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Respiratory Tract Infections ◽  
Innate Immune ◽  
Immune Memory ◽  
Proof Of Concept ◽  
Respiratory Epithelial Cells ◽  
Bronchial Epithelial ◽  
Previous Contact ◽  
Tract Infections ◽  
Respiratory Epithelial

Abstract Human bronchial epithelial cells play a key role in airway immune homeostasis. We hypothesized that these sentinel cells can remember a previous contact with pathogen compounds and respond nonspecifically to reinfection, a phenomenon called innate immune memory. We demonstrated that their pre-exposure to Pseudomonas aeruginosa flagellin modify their inflammatory response to a second, non-related stimulus, including live pathogens or lipopolysaccharide. Using histone acetyltransferase and methyltransferase inhibitors, we showed that this phenomenon relied on epigenetic regulation. This report is a major breakthrough in the field of multi-microbial respiratory tract infections, wherein control of inflammatory exacerbations is a major therapeutic issue.

scholarly journals Pharmacological activation of STING blocks SARS-CoV-2 infection

2021 ◽  
Vol 6 (59) ◽  
pp. eabi9007
Author(s):  
Minghua Li ◽  
Max Ferretti ◽  
Baoling Ying ◽  
Hélène Descamps ◽  
Emily Lee ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Innate Immune ◽  
Delayed Response ◽  
Respiratory Epithelial Cells ◽  
Bronchial Epithelial ◽  
Effective Interventions ◽  
Global Pandemic ◽  
Cyclic Dinucleotides ◽  
Respiratory Epithelial

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.

scholarly journals Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells

Allergy ◽  
2015 ◽  
Vol 70 (8) ◽  
pp. 910-920 ◽  
Author(s):  
M. Contoli ◽  
K. Ito ◽  
A. Padovani ◽  
D. Poletti ◽  
B. Marku ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Innate Immune ◽  
Th2 Cytokines ◽  
Innate Immune Responses ◽  
Respiratory Epithelial Cells ◽  
Respiratory Epithelial

scholarly journals Bronchial epithelial DNA methyltransferase 3b dampens pulmonary immune responses during Pseudomonas aeruginosa infection

2021 ◽  
Vol 17 (4) ◽  
pp. e1009491
Author(s):  
Wanhai Qin ◽  
Xanthe Brands ◽  
Cornelis van ’t Veer ◽  
Alex F. de Vos ◽  
Jean-Claude Sirard ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Dna Methyltransferase ◽  
Alveolar Epithelial Cells ◽  
Negative Bacterium ◽  
Respiratory Epithelial Cells ◽  
Bronchial Epithelial ◽  
Gram Negative ◽  
Respiratory Epithelial

DNA methyltransferase (Dnmt)3b mediates de novo DNA methylation and modulation of Dnmt3b in respiratory epithelial cells has been shown to affect the expression of multiple genes. Respiratory epithelial cells provide a first line of defense against pulmonary pathogens and play a crucial role in the immune response during pneumonia caused by Pseudomonas (P.) aeruginosa, a gram-negative bacterium that expresses flagellin as an important virulence factor. We here sought to determine the role of Dntm3b in respiratory epithelial cells in immune responses elicited by P. aeruginosa. DNMT3B expression was reduced in human bronchial epithelial (BEAS-2B) cells as well as in primary human and mouse bronchial epithelial cells grown in air liquid interface upon exposure to P. aeruginosa (PAK). Dnmt3b deficient human bronchial epithelial (BEAS-2B) cells produced more CXCL1, CXCL8 and CCL20 than control cells when stimulated with PAK, flagellin-deficient PAK (PAKflic) or flagellin. Dnmt3b deficiency reduced DNA methylation at exon 1 of CXCL1 and enhanced NF-ĸB p65 binding to the CXCL1 promoter. Mice with bronchial epithelial Dntm3b deficiency showed increased Cxcl1 mRNA expression in bronchial epithelium and CXCL1 protein release in the airways during pneumonia caused by PAK, which was associated with enhanced neutrophil recruitment and accelerated bacterial clearance; bronchial epithelial Dnmt3b deficiency did not modify responses during pneumonia caused by PAKflic or Klebsiella pneumoniae (an un-flagellated gram-negative bacterium). Dnmt3b deficiency in type II alveolar epithelial cells did not affect mouse pulmonary defense against PAK infection. These results suggest that bronchial epithelial Dnmt3b impairs host defense during Pseudomonas induced pneumonia, at least in part, by dampening mucosal responses to flagellin.

scholarly journals Human Metapneumovirus Establishes Persistent Infection in the Lungs of Mice and Is Reactivated by Glucocorticoid Treatment

2009 ◽  
Vol 83 (13) ◽  
pp. 6837-6848 ◽  
Author(s):  
Yuru Liu ◽  
Debra L. Haas ◽  
Spencer Poore ◽  
Sanjin Isakovic ◽  
Michelle Gahan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Metapneumovirus ◽  
Respiratory Epithelial Cells ◽  
Glucocorticoid Treatment ◽  
Hmpv Infection ◽  
Neuronal Processes ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Respiratory Epithelial

ABSTRACT Human metapneumovirus (HMPV) has been identified as a worldwide agent of serious upper and lower respiratory tract infections in infants and young children. HMPV is second only to respiratory syncytial virus (RSV) as a leading cause of bronchiolitis, and, like RSV, consists of two major genotypes that cocirculate and vary among communities year to year. Children who have experienced acute HMPV infection may develop sequelae of wheezing and asthma; however, the features contributing to this pathology remain unknown. A possible mechanism for postbronchiolitis disease is that HMPV might persist in the lung providing a stimulus that could contribute to wheezing and asthma. Using immunohistochemistry to identify HMPV-infected cells in the lungs of mice, we show that HMPV mediates biphasic replication in respiratory epithelial cells then infection migrates to neuronal processes that innervate the lungs where the virus persists with no detectable infection in epithelial cells. After glucocorticoid treatment, the virus is reactivated from neural fibers and reinfects epithelial cells. The findings show that HMPV persists in neural fibers and suggest a mechanism for disease chronicity that has important implications for HMPV disease intervention strategies.

scholarly journals FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

2013 ◽  
Vol 190 (4) ◽  
pp. 1603-1613 ◽  
Author(s):  
Frederik Seiler ◽  
Jan Hellberg ◽  
Philipp M. Lepper ◽  
Andreas Kamyschnikow ◽  
Christian Herr ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Epithelial Cells ◽  
Innate Immune ◽  
Respiratory Epithelial Cells ◽  
Immune Mechanisms ◽  
Foxo Transcription Factors ◽  
Respiratory Epithelial

scholarly journals Respiratory Viruses Augment the Adhesion of Bacterial Pathogens to Respiratory Epithelium in a Viral Species- and Cell Type-Dependent Manner

2006 ◽  
Vol 80 (4) ◽  
pp. 1629-1636 ◽  
Author(s):  
Vasanthi Avadhanula ◽  
Carina A. Rodriguez ◽  
John P. DeVincenzo ◽  
Yan Wang ◽  
Richard J. Webby ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Respiratory Epithelial Cells ◽  
Bronchial Epithelial ◽  
Immortalized Cell ◽  
Respiratory Epithelial ◽  
Primary Bronchial Epithelial Cells ◽  
Small Airway Epithelial Cells

ABSTRACT Secondary bacterial infections often complicate respiratory viral infections, but the mechanisms whereby viruses predispose to bacterial disease are not completely understood. We determined the effects of infection with respiratory syncytial virus (RSV), human parainfluenza virus 3 (HPIV-3), and influenza virus on the abilities of nontypeable Haemophilus influenzae and Streptococcus pneumoniae to adhere to respiratory epithelial cells and how these viruses alter the expression of known receptors for these bacteria. All viruses enhanced bacterial adhesion to primary and immortalized cell lines. RSV and HPIV-3 infection increased the expression of several known receptors for pathogenic bacteria by primary bronchial epithelial cells and A549 cells but not by primary small airway epithelial cells. Influenza virus infection did not alter receptor expression. Paramyxoviruses augmented bacterial adherence to primary bronchial epithelial cells and immortalized cell lines by up-regulating eukaryotic cell receptors for these pathogens, whereas this mechanism was less significant in primary small airway epithelial cells and in influenza virus infections. Respiratory viruses promote bacterial adhesion to respiratory epithelial cells, a process that may increase bacterial colonization and contribute to disease. These studies highlight the distinct responses of different cell types to viral infection and the need to consider this variation when interpreting studies of the interactions between respiratory cells and viral pathogens.

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