Modulation of Pediatric Sepsis by Virus Persistence

Project Summary Sepsis-induced multi-organ dysfunction syndrome (MODS) is a heterogeneous condition with distinct phenotypes, including hypoactive immune response ("immunoparalysis") and hyperinflammation. There remains a significant unmet need for novel biomarkers that help to define sepsis phenotype and predict responses to immunomodulatory therapy for patients with sepsis. Laboratory evidence of persistent viral infection may be such a biomarker. Common DNA viruses, such as human cytomegalovirus, Epstein-Barr virus, other human herpesviruses, and human adenoviruses, persist in their host following the resolution of acute infection. Work from the proposed research team and others indicates that reactivation of persistent DNA viruses has been linked to increased systemic inflammation and worse clinical outcomes in adults and children with sepsis. The research team's recently published work also suggests that virus persistence itself, even in the absence of reactivation, can affect outcomes of sepsis in children. Additional published and preliminary data from the Principal Investigator's laboratory indicates that DNA virus persistence, again even in the absence of reactivation, affects outcomes of subsequent challenges such as bacterial coinfection and bone marrow transplantation. Immunomodulatory strategies are currently being evaluated for treatment of pediatric patients with sepsis in the NIH-funded Personalized Immunomodulation in Sepsis-Induced MODS (PRECISE) study, including immunostimulatory therapy with GM-CSF for immunoparalysis (GRACE-2; NCT05266001) and anti-inflammatory therapy with anakinra administration for severe inflammation (TRIPS; NCT05267821). The therapeutic potential of those immunomodulatory therapies may also be influenced by virus persistence, particularly if they increase risk for virus reactivation. The overall hypothesis addressed by the research in the proposed project is that persistent infection with one or more DNA viruses worsens clinical outcomes and decreases response to immunomodulatory therapy in pediatric patients with sepsis. Aims 1 and 2 will test that hypothesis using clinical data and biorepository samples from the PRECISE study, evaluating virus status by detecting virus-specific antibody and viral DNAemia and determining whether virus status correlates with sepsis phenotype, clinical outcomes, measures of inflammation (serum concentrations of pro-inflammatory cytokines), and response to immunomodulatory therapy. Aim 3 will evaluate potential mechanisms underlying those effects, such as epigenetic modifications affecting pro-inflammatory cytokine expression, in a mouse model of persistent viral infection followed by Klebsiella pneumoniae sepsis. This approach to defining virus status as a determinant of sepsis phenotype and outcomes will provide valuable insight into the pathogenesis of sepsis and guidance for development of novel patient-targeted therapies.