RNA profiles in extracellular vesicles from severe sepsis and meningitis patients reveal pathogen-specific immune signatures in meningococcal versus pneumococcal infections.

This study investigates host-pathogen interactions by comparing RNA profiles in plasma extracellular vesicles (EVs) from patients with severe sepsis or meningitis caused by Neisseria meningitidis with profiles from patients with systemic Streptococcus pneumoniae infections. At hospital admission both bacteria may present with similar symptoms, making early differentiation difficult. We have focused on EVs, as they function as active mediators of intercellular communication in the circulation. Plasma samples from patients with meningococcal septic shock, meningococcal meningitis, pneumococcal infection, and healthy controls were analyzed. EVs were isolated by size exclusion chromatography, and EV derived RNA isolated by ExoRNeasy for examination by microarray. Ingenuity Pathway Analysis searched for pathogen specific EV-RNA signatures and predicted effects on biofunctions and canonical pathways. Additionally, the plasma EV-RNA profiles from the meningococcal sepsis patients were compared with previously published transcriptomic data from post-mortem organ tissue from patients who died from N. meningitidis sepsis. Transcriptomic profiling detected 14,909 EV-RNAs, enriched for small RNAs and canonical markers, and distinct molecular signatures across the disease groups. Patients with meningococcal septic shock displayed the most pronounced transcriptomic dysregulation, followed by milder changes in meningococcal meningitis, whereas pneumococcal disease exhibited broad pathway inhibition. S100A12, S100A8/A9 and AQP9 and plasma calprotectin were consistently elevated in all patient groups. Pathway analysis demonstrated strong activation of inflammatory and immune signaling in meningococcal septic shock, weaker activation in meningitis, and inhibition of multiple pathways in pneumococcal infection. Importantly, EV-RNA plasma profiles from meningococcal septic shock patients closely mirrored transcriptomic patterns in postmortem organ tissues detected in a previous study of lethal meningococcal shock patients. This study is the first to identify specific EV-RNA profiles in plasma from patients infected with N. meningitidis or S. pneumoniae. The profiles showed marked differences between the two species. In meningococcal sepsis, EV-RNA signatures in plasma were aligned with transcriptomic patterns observed in major organs suggesting that circulating EV-RNA may reflect both systemic and tissue level host responses. These findings support EV profiling as a non-invasive approach for identifying pathogen specific responses, with potential to enhance early diagnostics and clinical management of sepsis.