Divya Dubey – NIH Trainee 2024-2025
Research Progress: Our current research investigates how alveolar macrophages (AMs) are influenced by Type I interferon (IFN) / (IFNβ). Our previous work has shown an upregulation in IFN dependent gene signatures in AMs upon previous exposure to/ training with BCG vaccination before Mtb challenge. To investigate how IFN activation by BCG vaccination prompts AM remodeling, we utilized a type I IFN overexpression model with a knockout of SP140 on C57BL/6J mouse background. We found that like SP140-/- BMDMs, AMs also demonstrate an overexpression of type I IFN upon LPS and Mtb stimulation. We further investigated their responses to exogenous type I IFN in the background and found that surprisingly, SP140-/- AM cytokine responses are enhanced by heightened IFN signaling but lower compared to WT. We are currently in the process of investigating the cellular mechanisms behind this phenomenon in hopes that it uncovers how AM’s innate sensing of IFNb affects its response to Mtb. Notably, we have also found a marked difference in WT and SP140-/- AM TNF and IL-6 cytokine induction upon LPS stimulation. TNF is induced faster and more sustained in SP140-/- AMs compared to IL-6. Our ongoing research aims to delve further into how AMs respond to IFNβ mechanistically, in the context of TB, and examining the temporal mode that most significantly influences cytokine induction between IFNg and IFNb. We also hope to apply what we learn from the mouse models to human BAL samples (collaboration: IMPAc-TB) that we will be performing epigenetic analysis on. Through these investigations, we aim to deepen our understanding of AM remodeling by IFNβ and its implications in Tb infection.