Streptococcus pneumoniae binds to host GAPDH on dying lung epithelial cells worsening secondary infection following influenza

• Published in: Cell reports (Cambridge) Vol. 35; no. 11; p. 109267
• Main Authors: Park, Sang-Sang, Gonzalez-Juarbe, Norberto, Riegler, Ashleigh N, Im, Hansol, Hale, Yvette, Platt, Maryann P, Croney, Christina, Briles, David E, Orihuela, Carlos J
• Format: Journal Article
• Language: English
• Published: United States Elsevier 15.06.2021
• Subjects: A549 Cells; Animals; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Cell Death; Coinfection - microbiology; Coinfection - pathology; Coinfection - virology; Epithelial Cells - microbiology; Epithelial Cells - pathology; Female; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Host-Pathogen Interactions; Humans; influenza; Influenza, Human - complications; Lung - pathology; Mice; Mice, Inbred C57BL; pneumococcus; pneumonia; Protein Binding; Protein Structure, Secondary; PspA; Streptococcus pneumoniae; Streptococcus pneumoniae - metabolism; super-infection; influenza; pathogenesis; pneumococcus; PspA; synergy; cell death; pneumonia; super-infection; pneumolysin; Streptococcus pneumoniae; necroptosis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109267

Streptococcus pneumoniae (Spn) alone and during co-infection with influenza A virus (IAV) can result in severe pneumonia with mortality. Pneumococcal surface protein A (PspA) is an established virulence factor required for Spn evasion of lactoferricin and C-reactive protein-activated complement-mediated killing. Herein, we show that PspA functions as an adhesin to dying host cells. We demonstrate that PspA binds to host-derived glyceraldehyde-3-phosphate dehydrogenase (GAPDH) bound to outward-flipped phosphatidylserine residues on dying host cells. PspA-mediated adhesion was to apoptotic, pyroptotic, and necroptotic cells, but not healthy lung cells. Using isogenic mutants of Spn, we show that PspA-GAPDH-mediated binding to lung cells increases pneumococcal localization in the lower airway, and this is enhanced as a result of pneumolysin exposure or co-infection with IAV. PspA-mediated binding to GAPDH requires amino acids 230-281 in its α-helical domain with intratracheal inoculation of this PspA fragment alongside the bacteria reducing disease severity in an IAV/Spn pneumonia model.