Dual Acting Neuraminidase Inhibitors Open New Opportunities to Disrupt the Lethal Synergism between Streptococcus pneumoniae and Influenza Virus

Abstract

Secondary infections with Streptococcus pneumoniae cause severe pneumonia and enhance lethality during influenza epidemics and pandemics. Structural and functional similarities with viral neuraminidase (NA) suggest that the highly prevalent pneumococcal NAs, NanA and NanB, might contribute to this lethal synergism by supporting viral replication and that dual acting NA inhibitors (NAIs) will disrupt it. To verify this hypothesis, NanA and NanB were expressed in E. coli. After confirming their activity in enzyme assays, in vitro models with influenza virus A/Jena/8178/09 (Jena/8178) and the recombinant NanA or NanB (rNanA and rNanB) were established in A549 and MDCK cells to mimic the role of these pneumococcal NAs during co-infection. Studies on the influence of both NAs on viral receptor expression, spread, and yield revealed a distinct effect of NanA and NanB on viral replication in these in vitro models. Both enzymes were able to support Jena/8178 replication at certain concentrations. This synergism was disrupted by the NAIs oseltamivir, DANA, katsumadain A, and artocarpin exerting an inhibitory effect on viral NA and NanA. Interestingly, katsumadain A and artocarpin inhibited rNanA and rNanB similarly. Zanamivir did not show activity. These results demonstrate a key role of pneumococcal NAs in the lethal synergism with influenza viruses and reveal opportunities for its effective disruption.

Host‐pathogen kinetics during influenza infection and coinfection: insights from predictive modeling

“…There was no pre‐defined hypothesis or evidence for this increase, but its inclusion in the model was critical. This novel hypothesis subsequently guided several in vitro experimental studies, where at least two potential underlying mechanisms were discovered. First, S. aureus , another common coinfecting bacteria, was shown to inhibit IFN signaling in influenza‐infected cells, which resulted in increased virus production .…”

Editorial

“…Staphylococcus aureus , Streptococcus pneumoniae and Haemophilus influenzae are the major bacteria associated in simultaneous co-infection with influenza virus [2]. In vitro studies have shown that S. pneumoniae enhances influenza replication by producing a neuraminidase [3]. It has been suggested that it is difficult to evaluate the importance of viral/bacterial co-infection in the early years of an influenza pandemic due to low immunity.…”

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

“…Moreover, results from previous studies showed that bacterial NA rescues influenza virus replication from inhibition by zanamivir328. In contrast, both 5 and 27 (50 µM) reduce the viral yield in A549 cells in the presence of NanA of DSM20566 from 100 to 31.8 ± 4.5% and 7.4 ± 1.2%.…”

“…The inhibition of the NA of whole 8178/09 and WSN/33 preparations and recombinant NanA of pneumococcus DSM205663 were studied. The readout was performed with a microplate reader (FLUOstar Omega, BMG Labtech GmbH, Ortenberg, Germany).…”