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 2

IAV lung infection disrupts AWL secretion in live alveoli.

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IAV lung infection disrupts AWL secretion in live alveoli. (A) Low-power...
(A) Low-power (inset) and high-power confocal images show fluorescence of tetramethylrhodamine-conjugated (TRITC-conjugated) dextran (70 kDa; 10 mg/mL; yellow) in live alveoli (magenta) at 10 minutes after alveolar dextran microinstillation. Note that dextran formed a thin layer against alveolar walls and pooled in structural alveolar niches (arrowheads). CR, calcein red-orange; alv, alveolar airspace. Scale bars: 50 (inset) and 20 μm. Images replicated in 40 mice. (B–E) Confocal images (B–D) and group data (E) show time-dependent change of alveolar dextran fluorescence in airspaces of live alveoli in lungs excised from mice that were untreated (B–D), top row, and E, filled circles; n = 4 mice) or intranasally instilled with IAV at 24 hours before imaging (B–D, bottom row, and E, open circles; n = 4 mice). Fluorescence of alveolar walls is not shown. Group data (E) represent mean ± SEM. For each mouse, mean dextran fluorescence was quantified at each of the 3 indicated time points in an imaging field containing at least 30 lung alveoli. *P < 0.05 vs. closed circles by 2-tailed t test. Scale bars: 50 μm.