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 1

IAV replication increases Spn in the airway.

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IAV replication increases Spn in the airway. (A and B) HBECs were infect...
(A and B) HBECs were infected with 150,000 PFU of IAV for 72 hours, followed by infection with 1,000 CFU of Spn (n = 4–16). (C) HBECs were infected with 100,000 PFU of IAV (pH1N1) and treated basally with 1 mM oseltamivir or 100 nM baloxavir marboxil for 72 hours, followed by infection with 1,000 CFU of Spn (n = 3–4). (D) HBECs were infected with 100,000 PFU of IAV (pH1N1) and then treated basally with 1 mM oseltamivir either 30 or 72 hours after IAV infection. After 72 hours of IAV infection, HBECs were apically infected with 1,000 CFU of Spn. Spn was quantified by vertical plating of apical washes collected after 6 hours of Spn infection (n = 4). All panels except C were analyzed by 1-way ANOVA with Dunnett’s (A) or Tukey’s (C and D) multiple-comparison test. **P < 0.01; ***P < 0.001; ****P < 0.0001. Brackets indicate median and interquartile range. Panel C was analyzed by Pearson’s correlation: r = 0.9348, 95% CI = 0.8645 to 0.9692, P < 0.0001. Open circles indicate mock IAV infection; closed circles indicate IAV infection. In panel B, magenta circles indicate rPR/8, green squares indicate H3N2, and blue triangles indicate pH1N1.