Role of Bacterial and Host DNases on Host-Pathogen Interaction duringStreptococcus suisMeningitis

Streptococcus suisis a zoonotic agent causing meningitis in pigs and humans. Neutrophils, as the first line of defense againstS. suisinfections, release neutrophil extracellular traps (NETs) to entrap pathogens. In this study, we investigated the role of the secreted nuclease A ofS. suis(SsnA) as a NET-evasion factor in vivo and in vitro. Piglets were intranasally infected withS. suisstrain 10 or an isogenicssnAmutant. DNase and NET-formation were analyzed in cerebrospinal fluid (CSF) and brain tissue. Animals infected withS. suisstrain 10 orS. suis10 Delta ssnAshowed the presence of NETs in CSF and developed similar clinical signs. Therefore, SsnA does not seem to be a crucial virulence factor that contributes to the development of meningitis in pigs. Importantly, DNase activity was detectable in the CSF of both infection groups, indicating that host nucleases, in contrast to bacterial nuclease SsnA, may play a major role during the onset of meningitis. The effect of DNase 1 on neutrophil functions was further analyzed in a 3D-cell culture model of the porcine blood-CSF barrier. We found that DNase 1 partially contributes to enhanced killing ofS. suisby neutrophils, especially when plasma is present. In summary, host nucleases may partially contribute to efficient innate immune response in the CSF.