Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole animal dual RNA-seq

Abstract

Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole animal in vivo dual RNA-seq approach, we identified pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis we identified host pathways known to be activated by pneumolysin, and discovered the importance of necroptosis for host survival. Inhibition of this pathway using the drugs necrostatin-5 or GSK872 increased host mortality during pneumococcal meningitis. On the side of the pathogen, we find that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence and that not all bacteria activate competence at the same time. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.

Competence remodels the pneumococcal cell wall providing resistance to fratricide and surface exposing key virulence factors

“…5E), comCDE mutants were shown to be attenuated in a mouse and zebrafish meningitis model. The key difference between these models is that in the superinfection model bacteria can immediately replicate without a clear bottleneck imposed by the host immune system (Liu et al, 2021), while the meningitis models take significant time from inoculation to colonization to dissemination (Jim et al, 2022; Schmidt et al, 2019). It will be interesting to see how competence and ComM-LytR regulated WTA synthesis plays a role in other disease models as well as in other clinical strains.…”

“…In addition, competence is also activated when cells are adhering to human epithelial cells (Aprianto et al, 2016), and during invasive disease as shown in several mouse and zebrafish models (Lin et al, 2020; Schmidt et al, 2019)(Jim et al, 2022). Indeed, competence development is a key pathogenic factor in pneumococcal meningitis (Jim et al, 2022; Schmidt et al, 2019). However, it is unclear how competence and fratricide play a role in pneumococcal virulence.…”

Streptococcus Pneumoniae Teichoic Acids

“…Therefore, in-depth study of virulence factors of S. pneumoniae is of great significance for the prevention and treatment of S. pneumoniae infection. The crucial virulence factors of S. pneumoniae include: Teichoic acids (TAs) [5] ,Capsular polysaccharide (CPS) [6] ,Pneumolysin(Ply) [7] and so on [8,9] , Among them, TAs is a key and conserved virulence factor. This review will concentrate on the biosynthesis, function and pathogenic mechanism of TAs in S. pneumoniae, the regulation of TAs biosynthesis, and the application of TAs in vaccine research.…”

“…Published by Francis Academic Press, UK -9-composed of pneumolysin toxoid-CbpA peptide recombinant fusion protein[J]. J Infect Dis, 2014, 209(7): 1116-1125.…”