Coronavirus disease 2019 (COVID-19) is a worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has affected millions of lives. Individuals who survive severe COVID-19 can experience sustained respiratory symptoms that persist for months after initial infection. In other airway diseases, abnormal airway mucus contributes to sustained airway symptoms. However, the impact of SARS-CoV-2 on airway mucus has received limited attention. In the current review, we assess literature describing the impact of SARS-CoV-2 on airway pathophysiology with specific emphasis on mucus production. Accumulating evidence suggests that the 2 major secreted airway mucin glycoproteins, MUC5AC and MUC5B, are abnormal in some patients with COVID-19. Aberrations in MUC5AC or MUC5B in response to SARS-CoV-2 infection are likely due to inflammation, though the responsible mechanisms have yet to be determined. Thus, we also provide a proposed model highlighting mechanisms that can contribute to acute and sustained mucus abnormalities in SARS-CoV-2, with an emphasis on inflammatory cells and mediators, including mast cells and histamine. Last, we bring to light the challenges of studying abnormal mucus production in SARS-CoV-2 infections and discuss the strengths and limitations of model systems commonly used to study COVID-19. The evidence to date suggests that ferrets, nonhuman primates, and cats may have advantages over other models to investigate mucus in COVID-19.

Acid‐sensing ion channel‐1a (ASIC1a) mediates H+‐gated current to influence normal brain physiology and impact several models of disease. Although ASIC2 subunits are widely expressed in brain and modulate ASIC1a current, their function remains poorly understood. We identified ASIC2a in dendrites, dendritic spines, and brain synaptosomomes. This localization depended on ASIC2a binding to PSD‐95 and matched that of ASIC1a, which does not bind PSD‐95. We found that ASIC2 and ASIC1a associated in brain, and through its interaction with PSD‐95, ASIC2 increased ASIC1a localization in dendritic spines. Loss of ASIC2 reduced the acid‐evoked elevation of [Ca2+]i in dendritic spines and impaired fear conditiong, both of which require ASIC1a. These results indicate that ASIC2 facilitates ASIC1a localization and function in dendritic spines and thereby fear‐related behavior.

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Mild airway acidification occurs in several airway diseases, including cystic fibrosis and asthma. However, the role of airway acidification in airway pathology is controversial. Here, we studied mucus secretion in piglets forty‐eight hours following an intra‐airway acid challenge. Airway submucosal glands of acid‐challenged piglets exhibited faulty submucosal gland secretion, with a retainment of mucin 5B (MUC5B) in the submucosal gland and decreased concentrations of MUC5B in lung lavage fluid following cholinergic stimulation. Concomitantly, intrapulmonary airways were obstructed with glycoprotein rich material under both basal and methacholine‐stimulated conditions. Blocking detection of acid with the diminazene aceturate, a small molecule that inhibits the acid‐sensing ion channel (ASIC), partially restored submucosal gland function and mitigated acid‐induced airway obstruction. These findings suggest that transient airway acidification significantly impacts mucus secretion and highlight diminazene aceturate as an agent beneficial in alleviating some mucus defects. Support or Funding Information HL119560, 1OT2OD023854

RNA Se que nci ng of Pori ne G a ngl i a a nd bra i nste m RNA Se que nci ng of Pori ne G a ngl i a a nd bra i nste m Ani ma l s. Ani ma l s. A total of 44 piglets (Yorkshire Landrace breed, 2-3 days of age) were fed commercial milk replacer (Soweena Litter Life) and allowed a 36-48-h acclimation period before interventions began. The University of Florida Animal Care and Use Committee approved all procedures. Procedures were completed in accordance with federal policies and guidelines. A total of 12 piglets were reserved for RNA sequencing experiments (6 male and 6 female). Ai rwa y i nsti l l a ti on Ai rwa y i nsti l l a ti on. After acclimation, piglets were anesthetized with 8% SevoThesia (Henry Schein). The piglets' airways were accessed with a laryngoscope; a laryngotracheal atomizer (MADgic) was passed directly beyond the vocal folds, as previously described to aerosolize either a 500 μl 0.9% saline control or 1% acetic acid in 0.9% saline solution to the airway. This procedure results in widespread distribution of aerosolized solutions throughout the piglet airway, including the lung. Consistent with acid as a cough-evoking stimulus acetic acid induced cough in 90% or greater of the piglets.