Rescue of alveolar wall liquid secretion blocks fatal lung injury due to influenza-staphylococcal coinfection
Stephanie Tang, … , Jahar Bhattacharya, Jaime L. Hook
Stephanie Tang, … , Jahar Bhattacharya, Jaime L. Hook
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(19):e163402. https://doi.org/10.1172/JCI163402.
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Research Article Pulmonology

Rescue of alveolar wall liquid secretion blocks fatal lung injury due to influenza-staphylococcal coinfection

Abstract

Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host defense to promote SA infection in lung alveoli, where fatal lung injury occurs, is not known. We addressed this issue using real-time determinations of alveolar responses to IAV in live, intact, perfused lungs. Our findings show that IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled SA. Loss of AWL secretion resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in the alveolar epithelium, and airspace liquid absorption was caused by stimulation of the alveolar epithelial Na+ channel (ENaC). Loss of AWL secretion promoted alveolar stabilization of inhaled SA, but rescue of AWL secretion protected against alveolar SA stabilization and fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled SA and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection.

Authors

Stephanie Tang, Ana Cassandra De Jesus, Deebly Chavez, Sayahi Suthakaran, Sarah K.L. Moore, Keshon Suthakaran, Sonya Homami, Raveen Rathnasinghe, Alison J. May, Michael Schotsaert, Clemente J. Britto, Jahar Bhattacharya, Jaime L. Hook

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Figure 6

IAV lung infection causes alveolar retention of inhaled SAGFP.

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IAV lung infection causes alveolar retention of inhaled SAGFP. Mice were...
Mice were pretreated with intranasal instillation of IAV or PBS as indicated, then intranasally instilled with SAGFP 24 hours later. For group data, circles indicate n and each represent 1 mouse. Bars represent mean ± SEM; *P < 0.05 as indicated by 2-tailed t test. (A–C) Low-power (inset) and high-power confocal images (A) show SAGFP fluorescence in live alveoli of intact, blood-perfused, IAV-infected mouse lungs, 1 hour after intranasal SAGFP instillation. Dashed lines delineate example alveolar walls (fluorescence not shown). Single and double arrows indicate SAGFP grouped as small clusters (SC) and microaggregates (MA), respectively. Group data show number (B) and size (C) of SCs and MAs in alveoli of lungs pretreated with PBS or IAV instillation. For B and C, SAGFP group number and size were quantified as means in at least 2 imaged fields of 30 alveoli each. Alv, example alveolar airspace. Scale bars: 50 (inset) and 10 μm. (D and E) Confocal images (D) show alveolar SAGFP fluorescence at 1 hour (left) and, in the same alveoli, at 3 hours (right) after SAGFP instillation. Arrowheads indicate example MAs that spontaneously lost all fluorescence, hence were cleared from alveoli. Group data (E) show the proportion of SAGFP MAs that maintained alveolar fluorescence, hence were retained in alveoli. For E, MAs were quantified as the mean proportion retained in at least 2 imaged fields of 30 alveoli each. Scale bars: 50 μm. (F) Content of viable SAGFP in lung homogenate at 3 hours after intranasal SAGFP instillation.