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 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

Bordetella pertussis Induces Interferon Gamma Production by Natural Killer Cells, Resulting in Chemoattraction by Respiratory Epithelial Cells

2020 ◽  
Author(s):  
Gerco den Hartog ◽  
Marcel A Schijf ◽  
Guy A M Berbers ◽  
Fiona R M van der Klis ◽  
Anne-Marie Buisman
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Bordetella Pertussis ◽  
Respiratory Epithelial Cells ◽  
Chemokine Production ◽  
Ifn Γ ◽  
Respiratory Epithelial

Abstract Background Whooping cough is caused by infection of the airways with Bordetella pertussis (Bp). As interferon gamma (IFN-γ) is essential for protective immunity against Bp, we investigated how IFN-γ is induced by Bp or the virulence antigens filamentous hemagglutinin adhesin, pertactin, or pertussis toxin, and how IFN-γ contributes to local immune responses in humans. Methods Peripheral blood mononuclear cells (PBMCs) from healthy donors and/or respiratory epithelial cells were stimulated with soluble antigens or inactivated intact Bp and the presence or absence of blocking antibodies or chemokines. Supernatants and cells were analyzed for IFN-γ and chemokine production, and lymphocyte migration was tested using epithelial supernatants. Results The soluble antigens failed to induce IFN-γ production, whereas inactivated Bp induced IFN-γ production. Natural killer (NK) cells were the main source of IFN-γ production, which was enhanced by interleukin 15. Epithelial–PBMC co-cultures showed robust IFN-γ–dependent CXCL9 and CXCL10 production by the epithelial cells following stimulation with IFN-γ and Bp. The epithelial-derived chemokines resulted in CXCR3-dependent recruitment of NK and T cells. Conclusions Inactivated Bp, but not antigens, induced potent IFN-γ production by NK cells, resulting in chemoattraction of lymphocytes toward the respiratory epithelium. These data provide insight into the requirements for IFN-γ production and how IFN-γ enhances local immune responses to prevent Bp-mediated disease.

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.

Review: Defensins and cathelicidins in lung immunity

2010 ◽  
Vol 16 (3) ◽  
pp. 151-159 ◽  
Author(s):  
Tesfaldet Tecle ◽  
Shweta Tripathi ◽  
Kevan L. Hartshorn
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Biological Activities ◽  
Large Family ◽  
Inflammatory Cells ◽  
Respiratory Epithelial Cells ◽  
Spectrum Activity ◽  
Respiratory Epithelial ◽  
Lung Immunity

Defensins were first identified in 1985 and are now recognized as part of a large family of antimicrobial peptides, divided into three categories: α-, β-, and θ-defensins. These defensin classes differ in structure, sites of expression and biological activities. Human α-defensins include peptides that are expressed primarily in neutrophils, whereas human β-defensins are widely expressed in epithelial cells, including those lining the respiratory tract. Defensins were first studied for their broad spectrum activity against bacteria, fungi and viruses; however, it is now clear that they also recruit inflammatory cells and promote innate and adaptive immune responses. Recent evidence shows that defensins have anti-inflammatory effects as well. Hence, defensins can participate in all phases of an immune response in the lung, including initial killing of pathogens and mounting — and resolution —- of an immune or inflammatory response. The cathelicidin, LL-37, is an antimicrobial peptide produced by neutrophils and respiratory epithelial cells that has similar roles in lung immunity as the defensins. A major challenge for the coming years will be to sort out the relative contributions of defensins and LL-37 to overall immune responses in the lung and to determine which of their many in vitro activities are most important for lung immunity.

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.

scholarly journals Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion

2019 ◽  
Vol 87 (11) ◽  
Author(s):  
C. P. Ahearn ◽  
C. Kirkham ◽  
L. D. Chaves ◽  
Y. Kong ◽  
M. M. Pettigrew ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Haemophilus Influenzae ◽  
Cell Invasion ◽  
Bacterial Cell ◽  
Alveolar Epithelial Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chronic Obstructive ◽  
Respiratory Epithelial Cells ◽  
Lower Airways ◽  
Respiratory Epithelial

ABSTRACT Nontypeable Haemophilus influenzae (NTHi) is the primary cause of bacterially induced acute exacerbations of chronic obstructive pulmonary disease (COPD). NTHi adheres to and invades host respiratory epithelial cells as a means to persist in the lower airways of adults with COPD. Therefore, we mined the genomes of NTHi strains isolated from the airways of adults with COPD to identify novel proteins to investigate their role in adherence and invasion of human respiratory epithelial cells. An isogenic knockout mutant of the open reading frame NTHI1441 showed a 76.6% ± 5.5% reduction in invasion of human bronchial and alveolar epithelial cells at 1, 3, and 6 h postinfection. Decreased invasion of the NTHI1441 mutant was independent of either intracellular survival or adherence to cells. NTHI1441 is conserved among NTHi genomes. Results of whole-bacterial-cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry experiments identified that NTHI1441 has epitopes expressed on the bacterial cell surface. Adults with COPD develop increased serum IgG against NTHI1441 after experiencing an exacerbation with NTHi. This study reveals NTHI1441 as a novel NTHi virulence factor expressed during infection of the COPD lower airways that contributes to invasion of host respiratory epithelial cells. The role in host cell invasion, conservation among strains, and expression of surface-exposed epitopes suggest that NTHI1441 is a potential target for preventative and therapeutic interventions for disease caused by NTHi.

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