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.

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.

Flagellin induces innate immune genes in bronchial epithelial cells in vivo: Role of TET2

2021 ◽  
Author(s):  
Wanhai Qin ◽  
Xanthe Brands ◽  
Cornelis Veer ◽  
Alex F. Vos ◽  
Brendon P. Scicluna ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Innate Immune ◽  
Bronchial Epithelial ◽  
Immune Genes ◽  
Innate Immune Genes

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 Immunobiotic Lactobacilli Improve Resistance of Respiratory Epithelial Cells to SARS-CoV-2 Infection

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1197
Author(s):  
Md. Aminul Islam ◽  
Leonardo Albarracin ◽  
Mikado Tomokiyo ◽  
Juan Carlos Valdez ◽  
Jacinto Sacur ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Poly I:C ◽  
Respiratory Pathogens ◽  
Respiratory Epithelial Cells ◽  
Beneficial Effects ◽  
In Vivo Experiments ◽  
Syncytial Virus ◽  
Respiratory Epithelial

Previously, we reported that immunomodulatory lactobacilli, nasally administered, beneficially regulated the lung antiviral innate immune response induced by Toll-like receptor 3 (TLR3) activation and improved protection against the respiratory pathogens, influenza virus and respiratory syncytial virus in mice. Here, we assessed the immunomodulatory effects of viable and non-viable Lactiplantibacillus plantarum strains in human respiratory epithelial cells (Calu-3 cells) and the capacity of these immunobiotic lactobacilli to reduce their susceptibility to the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immunobiotic L. plantarum MPL16 and CRL1506 differentially modulated IFN-β, IL-6, CXCL8, CCL5 and CXCL10 production and IFNAR2, DDX58, Mx1 and OAS1 expression in Calu-3 cells stimulated with the TLR3 agonist poly(I:C). Furthermore, the MPL16 and CRL1506 strains increased the resistance of Calu-3 cells to the challenge with SARS-CoV-2. L. plantarum MPL16 induced these beneficial effects more efficiently than the CRL1506 strain. Of note, neither non-viable MPL16 and CRL1506 strains nor the non-immunomodulatory strains L. plantarum CRL1905 and MPL18 could modify the resistance of Calu-3 cells to SARS-CoV-2 infection or the immune response to poly(I:C) challenge. To date, the potential beneficial effects of immunomodulatory probiotics on SARS-CoV-2 infection and COVID-19 outcome have been extrapolated from studies carried out in the context of other viral pathogens. To the best of our knowledge, this is the first demonstration of the ability of immunomodulatory lactobacilli to positively influence the replication of the new coronavirus. Further mechanistic studies and in vivo experiments in animal models of SARS-CoV-2 infection are necessary to identify specific strains of beneficial immunobiotic lactobacilli like L. plantarum MPL16 or CRL1506 for the prevention or treatment of the COVID-19.

scholarly journals Pneumococcal Interactions with Epithelial Cells Are Crucial for Optimal Biofilm Formation and ColonizationIn VitroandIn Vivo

2012 ◽  
Vol 80 (8) ◽  
pp. 2744-2760 ◽  
Author(s):  
Laura R. Marks ◽  
G. Iyer Parameswaran ◽  
Anders P. Hakansson
Keyword(s):  
Epithelial Cells ◽  
Biofilm Formation ◽  
Invasive Disease ◽  
Respiratory Epithelial Cells ◽  
Symptomatic Infection ◽  
Content Type ◽  
Abiotic Surfaces ◽  
Horizontal Spread ◽  
Respiratory Epithelial

ABSTRACTThe human nasopharynx is the main reservoir forStreptococcus pneumoniae(the pneumococcus) and the source for both horizontal spread and transition to infection. Some clinical evidence indicates that nasopharyngeal carriage is harder to eradicate with antibiotics than is pneumococcal invasive disease, which may suggest that colonizing pneumococci exist in biofilm communities that are more resistant to antibiotics. While pneumococcal biofilms have been observed during symptomatic infection, their role in colonization and the role of host factors in this process have been less studied. Here, we show for the first time that pneumococci form highly structured biofilm communities during colonization of the murine nasopharynx that display increased antibiotic resistance. Furthermore, pneumococcal biofilms grown on respiratory epithelial cells exhibited phenotypes similar to those observed during colonizationin vivo, whereas abiotic surfaces produced less ordered and more antibiotic-sensitive biofilms. The importance of bacterial-epithelial cell interactions during biofilm formation was shown using both clinical strains with variable colonization efficacies and pneumococcal mutants with impaired colonization characteristicsin vivo. In both cases, the ability of strains to form biofilms on epithelial cells directly correlated with their ability to colonize the nasopharynxin vivo, with colonization-deficient strains forming less structured and more antibiotic-sensitive biofilms on epithelial cells, an association that was lost when grown on abiotic surfaces. Thus, these studies emphasize the importance of host-bacterial interactions in pneumococcal biofilm formation and provide the first experimental data to explain the high resistance of pneumococcal colonization to eradication by antibiotics.

Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo

2001 ◽  
Vol 107 (2) ◽  
pp. 235-243 ◽  
Author(s):  
Scherer P. Sanders ◽  
Edward S. Siekierski ◽  
Stephen M. Richards ◽  
Jacqueline D. Porter ◽  
Farhad Imani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Epithelial Cells ◽  
Respiratory Epithelial Cells ◽  
Human Respiratory Epithelial Cells ◽  
Respiratory Epithelial ◽  
Oxide Synthase
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