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

SUMMARY 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.
In brief Park et al. demonstrate that pneumococcal surface protein A (PspA) acts as a bacterial adhesin. They show that PspA mediates Streptococcus pneumoniae binding to dying host cells via interactions with surface-bound host GAPDH. Pneumococcal localization in the lower airway is enhanced following pneumolysin- or influenza A virus (IAV)-mediated damage in a PspA-dependent manner.
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