Neutrophil-Airway Epithelial Interactions Result in Increased Epithelial Damage and Viral Clearance during Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of pediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology. Using an in vitro model of the differentiated airway epithelium, we found that the addition of physiological concentrations of neutrophils to RSV-infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilium loss, less tight junction expression (ZO-1), and more detachment of epithelial cells than is seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV-positive cells in cultures after neutrophil exposure than in preexposure cultures. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1 h) and neutrophil degranulation, with significantly greater cellular expression of CD11b and myeloperoxidase and higher levels of neutrophil elastase and myeloperoxidase activity in apical surface media than in media with mock-infected airway epithelial cells (AECs). We also recovered more apoptotic neutrophils from RSV-infected cultures (>40%) than from mock-infected cultures (<5%) after 4 h. The results of this study could provide important insights into the role of neutrophils in host response in the airway. IMPORTANCE This study shows that the RSV-infected human airway drives changes in the behavior of human neutrophils, including increasing activation markers and delaying apoptosis, that result in greater airway damage and viral clearance.

High-Throughput Screening for Drugs That Inhibit Papain-Like Protease in SARS-CoV-2

“…Further downstream characterization of hit compounds should include an investigation into their activity on the deubiquitinating (DUB) and deISGylation activity of PLpro, because this is a key activity that overlaps partially, but not completely, with proteolytic activity for CoV PLpro. 17 – 19 Indeed, some recent studies have focused primarily on targeting this activity to modulate the immune evasion of SARS-CoV-2. 20 – 22 In addition, because PLpro resides in a multidomain, membrane-bound protein, it is possible that compounds that inhibit the soluble protease may not have as great of an effect on the full nsp3 protein and therefore on viral replication.…”

Manipulating neutrophil degranulation as a bacterial virulence strategy

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Streptococcus pneumoniae serotype 22F infection in respiratory syncytial virus infected neonatal lambs enhances morbidity

“…Thus, if dual infection with Spn leads to enhanced neutrophil recruitment to the lungs over RSV alone, those cells could become also become infected and have their antiviral or antibacterial responses altered. RSV can lead to alterations in neutrophil interactions with airway epithelium and increase histopathology [ 53 ]. Myeloperoxidase is associated with neutrophil release and is known to reduce Spn burdens at the expensive of tissue damage during otitis [ 54 ].…”