Search

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MJT and SEE are authors on U.S. patent 8,883,174, “Stimulation of Innate Resistance of the Lungs to Infection with Synthetic Ligands.” MJT and SEE own stock in Pulmotect, Inc. All other authors declare that no conflicts of interest exist., (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lung epithelial cells are increasingly recognized to be active effectors of microbial defense, contributing to both innate and adaptive immune function in the lower respiratory tract. As immune sentinels, lung epithelial cells detect diverse pathogens through an ample repertoire of membrane-bound, endosomal, and cytosolic pattern-recognition receptors (PRRs). The highly plastic epithelial barrier responds to detected threats via modulation of paracellular flux, intercellular communications, mucin production, and periciliary fluid composition. Epithelial PRR stimulation also induces production of cytokines that recruit and sculpt leukocyte-mediated responses, and promotes epithelial generation of antimicrobial effector molecules that are directly microbicidal. The epithelium can alternately enhance tolerance to pathogens, preventing tissue damage through PRR-induced inhibitory signals, opsonization of pathogen-associated molecular patterns, and attenuation of injurious leukocyte responses. The inducibility of these protective responses has prompted attempts to therapeutically harness epithelial defense mechanisms to protect against pneumonias. Recent reports describe successful strategies for manipulation of epithelial defenses to protect against a wide range of respiratory pathogens. The lung epithelium is capable of both significant antimicrobial responses that reduce pathogen burdens and tolerance mechanisms that attenuate immunopathology. This manuscript reviews inducible lung epithelial defense mechanisms that offer opportunities for therapeutic manipulation to protect vulnerable populations against pneumonia.

Despite widespread infection prevention efforts, pneumonia remains the leading cause of death among patients with acute leukemia, due to complex disease- and treatment-dependent immune defects. We have reported that a single inhaled treatment with a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) induces protective mucosal defenses in mice against a broad range of pathogens. As Pam2-ODN-induced protection persists despite depletion of several leukocyte populations, we tested whether it could prevent pneumonia in a mouse model of acute myeloid leukemia (AML) remission induction therapy. Pam2-ODN prevented death due to pneumonia caused by Pseudomonas aeruginosa, Streptococcus pneumoniae, and Aspergillus fumigatus when mice were heavily engrafted with leukemia cells, had severe chemotherapy-induced neutropenia or both. Pam2-ODN also extended survival of pneumonia in NSG mice engrafted with primary human AML cells. Protection was associated with rapid pathogen killing in the lungs at the time of infection and with reduced pathogen burdens at distant sites at the end of observation. Pathogen killing was inducible directly from isolated lung epithelial cells and was not abrogated by the presence of leukemia cells or cytotoxic agents. Pam2-ODN had no discernible effect on replication rate, total tumor population, or killing by chemotherapy of mouse or human leukemia cells, either in vitro or in vivo. Taken together, we report that therapeutic stimulation of lung epithelial defenses robustly protects against otherwise lethal pneumonias despite the profound immune dysfunction associated with acute leukemia and its treatment. These findings may suggest an opportunity to protect this population during periods of peak vulnerability., (© 2016 by The American Society of Hematology.)