Lung stromal cell dynamics are altered by infection experience and ongoing antigen presentation following influenza re-challenge

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Stromal cells can be permanently altered by insults, a process termed trained immunity. Whether these cells contribute to protection or pathology in infections such as influenza a virus (IAV) is unclear. We hypothesise that trained stromal cells may participate in protective immunity by rapidly reactivating local memory T cells. We performed transcriptional analysis on sorted lung epithelial cells and fibroblasts isolated from naïve and IAV infected mice (primary, memory, and re-challenge timepoints). Stromal cell dynamics were investigated using flow cytometry and immunofluorescence including detecting infected cells via IAV Nucleoprotein (NP). The location of infection experienced stromal and immune cells in the lung was determined using RNAscope. RNA-sequencing analysis revealed enrichment in immune related genes at primary/memory and re‑challenge timepoints in lung stromal cells. Importantly, NP+ epithelial cells expressed more MHCII compared to NP-neg cells, suggesting enhanced communication with T cells. Using RNAscope, SpiB, a transcription factor that regulates genes involved in antigen processing/presentation, was found in lung epithelial cells of infected mice. SpiB+ cells were in close proximity to immune cells that form dense clusters. Interestingly, these microenvironmental changes were dependent on viral replication. A subset of NP+ universal fibroblasts (Ly6C+Sca1+) were identified early post infection. Strikingly, MHCII+ fibroblasts were more abundant following IAV re‑challenge compared to initial infection. Increased understanding of stromal cell trained immunity may enhance our ability to protect against respiratory infections.

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