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

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 pathogens side, 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/479878v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1214d1aorg.highwire.dtl.DTLVardef@14d0e8corg.highwire.dtl.DTLVardef@1f6133aorg.highwire.dtl.DTLVardef@685955_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIPneumolysin-specific host and bacterial responses as identified by whole animal dual RNA-seq, available at https://veeninglab.com/dual-danio C_LIO_LIDiscovery of a functional necroptosis or necroptosis-like pathway in zebrafish C_LIO_LIHeterogeneity in competence development during infection C_LIO_LICompetence development is an important virulence determinant C_LI