Current Projects
We model severe respiratory viral disease in mice using influenza viruses and, when possible, study human samples through collaborations with other research groups.
With these close collaborators, we have generated a number of large single-cell and spatial transcriptomic datasets in the mouse model of severe influenza infection and from human lung samples. We use these datasets to generate hypotheses about how fibroblasts are activated and the consequences of their activation for respiratory health.
Biological Factors Determining Immune Activity of Lung Fibroblasts
Lung fibroblasts are a heterogeneous group of cells that can acquire diverse activation states following infection and injury. We are interested in defining the biological factors that determine how a fibroblast responds. These factors might include the location or tissue environment in which they reside, the stage of lung development, and the exposure history of the individual (including infectious and other environmental insults).
Location - Different fibroblast lineages are localized to specific functional compartments in the respiratory tract, including the conducting airways, blood vessels, and the alveoli carrying out gas exchange. We hypothesize that location of these fibroblasts is an important determinant of how they respond to respiratory viral infection. We use a combination of immunological techniques, such as flow cytometry, and tissue imaging to map and dissect these responses.
Age - Fibroblasts undergo dramatic changes in the developing lung with respect to their phenotypes and activities. It is unknown whether the immunological activity of fibroblasts also changes during lung development, adulthood, and aging. We hypothesize that the immunological activity of lung fibroblasts changes with age to calibrate the host defense strategy - tolerant to or resistant against viral infection. We use in vivo models of infection and in vitro models with primary lung fibroblasts to define age-dependent changes in fibroblast activity.
Analysis of distinct lung fibroblast lineages (Alveolar, Adventitial, Peribronchial) by flow cytometry
Mechanisms of Fibroblast Activation and Turnover
Fibroblasts are sometimes referred to as the “cockroaches of cells.” They are resilient, can survive harsh conditions, and can be invasive. Just as important to understanding how the fibroblasts get activated is determining how these cells deactivate or turnover. We are interested in defining the cell intrinsic mechanisms of fibroblast activation and turnover focusing on innate immune sensors that may promote activation and/or initiate distinct forms of regulated cell death. We use a combination of in vitro cell culture systems of primary lung fibroblasts and genetic tools in mouse models of infection to define the role of specific cell-intrinsic factors in regulating fibroblast activation and cell death.
Immunofluorescence imaging of lung fibroblasts labeled with a marker of inflammatory cell death
Activated Fibroblasts in Post-viral Lung Disease
Severe respiratory viral infections, including influenza, can have lasting impacts on lung structure and function and can result in post-viral disease, long after the virus is gone. Fibroblasts have important roles in repairing damaged tissue, but they also contribute to chronic lung diseases, such as pulmonary fibrosis. We are interested in determining how lung fibroblasts activated following severe influenza virus infection contribute to post-viral disease and their long-term impacts on respiratory health. Current projects are exploring fibroblast-specific therapeutic targets to prevent or reverse post-viral lung disease and the potential role of these activated lung fibroblast in promoting metastatic lung cancer.
