Myeloid-derived suppressor cells modulate disease severity in children with viral lower respiratory tract infections

Project Summary Severe lower respiratory tract infection (LRTI) due to viral pathogens remains one of the most common causes of death for young children worldwide. Current management of patients with viral-induced LRTI focuses on supportive care, but outcomes may be improved by augmenting the host immune response to fight the virus and regain immune homeostasis. A growing body of literature suggests that children with severe viral LRTI have an impaired adaptive immune response, specifically decreased T cell proliferation and cytokine production. Myeloid- derived suppressor cells (MDSC) are a heterogeneous cell population that expand during inflammatory conditions and potently inhibit T cell proliferation and function. MDSC have been extensively studied in adult oncologic populations where clinical trials show promising results of improved outcomes by inhibiting MDSC as part of chemotherapy and anti-tumor vaccine treatment regimens. Our group has identified significant increases in the frequency of MDSC populations in children with septic shock and COVID-19 and demonstrated associations between increased percentages of MDSC and worse clinical outcomes. However, it is unknown what role MDSC play in children with viral-induced severe LRTI. The overall goal of this proposal is to identify MDSC as contributors to the immune response in children with viral LRTI and identify mechanistic pathways as potential therapeutic targets for future investigations. Our central hypothesis is that increased frequency of MDSC will be associated with worse clinical outcomes and decreased numbers of CD4+ and CD8+ T cells in children with viral LRTI, and that pediatric MDSC-induced T cell suppression is reversible through inhibition of the PD-1 pathway. The proposed experiments will involve blood sampling of children with PCR-confirmed viral LRTI to characterize the dynamics of MDSC and lymphocyte populations during hospitalization. We will also use our in vitro model of MDSC induced from pediatric peripheral blood mononuclear cells and select patient samples to establish the PD-1 pathway as an important mechanism of MDSC-mediated inhibition of T cell proliferation and cytokine production in children. This career development award will generate the necessary data to inform the design of future studies of the pediatric immune response in severe lower respiratory tract infections and will equip me with the necessary tools to achieve independence as a patient- oriented clinician-scientist.