Influenza A–induced cystic fibrosis transmembrane conductance regulator dysfunction increases susceptibility to Streptococcus pneumoniae
Erin Y. Earnhardt, Jennifer L. Tipper, Adonis D’Mello, Ming-Yuan Jian, Elijah S. Conway, James A. Mobley, Carlos J. Orihuela, Hervé Tettelin, Kevin S. Harrod
Erin Y. Earnhardt, Jennifer L. Tipper, Adonis D’Mello, Ming-Yuan Jian, Elijah S. Conway, James A. Mobley, Carlos J. Orihuela, Hervé Tettelin, Kevin S. Harrod
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Research Article Infectious disease Virology

Influenza A–induced cystic fibrosis transmembrane conductance regulator dysfunction increases susceptibility to Streptococcus pneumoniae

Abstract

Influenza A virus (IAV) infection is commonly complicated by secondary bacterial infections that lead to increased morbidity and mortality. Our recent work demonstrates that IAV disrupts airway homeostasis, leading to airway pathophysiology resembling cystic fibrosis disease through diminished cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we use human airway organotypic cultures to investigate how IAV alters the airway microenvironment to increase susceptibility to secondary infection with Streptococcus pneumoniae (Spn). We observed that IAV-induced CFTR dysfunction and airway surface liquid acidification is central to increasing susceptibility to Spn. Additionally, we observed that IAV induced profound transcriptional changes in the airway epithelium and proteomic changes in the airway surface liquid in both CFTR-dependent and -independent manners. These changes correspond to multiple diminished host defense pathways and altered airway epithelial function. Collectively, these findings highlight both the importance of CFTR function during infectious challenge and demonstrate a central role for the lung epithelium in secondary bacterial infections following IAV.

Authors

Erin Y. Earnhardt, Jennifer L. Tipper, Adonis D’Mello, Ming-Yuan Jian, Elijah S. Conway, James A. Mobley, Carlos J. Orihuela, Hervé Tettelin, Kevin S. Harrod

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Figure 4

IAV increases Spn in the airway by inducing CFTR dysfunction.

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IAV increases Spn in the airway by inducing CFTR dysfunction. (A) Non-CF...
(A) Non-CF and CFTRΔ508-HBECs were infected with 100,000 PFU of IAV for 72 hours, followed by infection with 1,000 CFU of Spn. Spn was quantified by vertical plating of apical washes after 6 hours of Spn infection (n = 4). (B) Non-CF HBECS were infected with IAV and basally treated with 10 μM lumacaftor and tezacaftor at the time of IAV infection, and then basally treated with 10 μM ivacaftor overnight before Spn infection. After 72 hours of IAV infection, HBECs were infected with Spn for 6 hours. Spn was quantified by vertical plating of apical washes (n = 3–4). (C) CFTRΔ508-HBECs were infected with 100,000 PFU of IAV and basally treated with 10 μM lumacaftor and tezacaftor at the time of IAV infection, and then basally treated with 10 μM ivacaftor overnight before Spn infection. After 72 hours of IAV infection, HBECs were infected with Spn for 6 hours. Spn was quantified by vertical plating of apical washes (n = 4). Panel A is representative of 2 independent experiments, panel B is representative of 3 independent experiments, and the experiment in panel C was conducted once due to limited availability of CFTRΔ508-HBECs. All panels were analyzed by 1-way ANOVA with Bonferroni’s (A) or Tukey’s (B and C) multiple-comparison test. *P < 0.05; ****P < 0.0001. Brackets indicate median and interquartile range. Open circles indicate mock IAV infection; closed circles indicate IAV infection.