Journal Article

Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis

Bierwagen, Jeff, Sewald, Katherina, Wiegand, Marie, Laakmann, Katrin, Bertrams, Wilhelm, Schulte, Leon N., Dorna, Jens, Preußer, Christian, Limburg, Hannah, Pogge von Strandmann, Elke, Jonigk, Danny, Böttcher-Friebertshäuser, Eva, Heimerl, Thomas, Herbel, Stefanie Muriel, Braun, Armin, Schmeck, Bernd, Danov, Olga, Bauer, Stefan, Jung, Anna Lena

2023

Overview

Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles ( Legionella   pneumophila , Klebsiella   pneumoniae , Escherichia coli , Salmonella   enterica , Streptococcus   pneumoniae ) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella , E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella , E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. 7FMb6rvPxRFWumGrBQKEMq Video Abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adaptor Proteins, Vesicular Transport / Alveolar epithelial cell / Alveoli / Antiviral drugs / Bacteria / Bacterial and viral co-infection / Bacterial vesicles / Biomedical and Life Sciences / Cell Biology / Cell culture / Cell interactions / Cytokines / Cytokines and Growth Factors / Epithelial cells / Escherichia coli / Extracellular Vesicles / Extracellular Vesicles in Intercellular Communication / Gram-negative bacteria / Gram-positive bacteria / Humans / Immune response / Influenza / Influenza A / Klebsiella / Life Sciences / Macrophage / Macrophages / Membrane vesicles / Molecular weight / Myxovirus resistance proteins / NF-κB protein / Outer membrane vesicles / Pathogens / Penicillin / Phosphorylation / Pneumonia / Protein-Ligand Interactions / Proteins / Receptors / Replication / Salmonella / Stat1 protein / Streptococcus infections / TLR4 protein / Toll-Like Receptor 4 / Toll-like receptors / Viral infections / Virus Replication