Research

Infection is a top cause of early-life (0-5 years old) mortality, with viruses causing up to 19% of infant infection-related deaths. CD8 T are critical for anti-viral responses but they are also implicated in immunopathology. Despite being the top cause of infant hospitalizations, standard of care treatment for viral bronchiolitis is primarily limited to supportive care. Although monoclonal antibodies and maternal vaccinations are starting to roll out, there are limitations to these and no standard use of treatments to alter/fine tune host response. The molecular features that define optimal or deleterious host responses in early life are still not well understood.

Neonatal CD8 T cells proliferate and die faster than those of adults. The mechanisms that regulate these phenotypes are unclear. Our lab has discovered that neonatal CD8 T cells have quick but short lived onset of effector functions, including production of effector molecules like TNFa. Additionally we found that CD8 T cells have a switch to glycolytic metabolism and a unique transcription factor landscape.

We aim to define:

1. How CD8 T cell functions change in an age-related matter during health and critical illness, with a focus on severe viral bronchiolitis in early-life.
2. Molecular targets that can fine tune immune responses in critically ill children.

Our lab uses human blood and respiratory samples in vitro to understand phenotype and function of immune cells during health and severe viral bronchiolitis. Specifically, we aim to define mechanisms driving altered CD8 T cell signaling, effector functions and cell fate and how these are impacted during severe viral disease and vaccine responses. Using state of the art single cell and flow cytometry technologies and extremely small volume samples from pediatric patients, we aim to develop fine-tuned functional and phenotypic assays to find targetable molecular signatures.

Understanding the biology of early-life immune cells, including CD8 T cells, is fundamental to advancing new therapies that can improve outcomes and prevent severe childhood viral infections. This research will lead to critical insights into the basis for developmentally programmed cytotoxic T-cell responses and roles for specific molecular pathways, such as mTOR and TNF, in driving immune responses in early-life critical illness. Our work will provide important new insights for future large-scale studies of early-life responses to infection and vaccination. Also it will advance our understanding about whether specific molecular pathways are tunable targets for therapeutically modulating immune responses to improve early-life infection and vaccination outcomes.

Our overall goal is to identify pediatric patients at risk for immunopathology, including as a consequence of viral respiratory infections, and to improve immune responses during critical illness and after immunization.