Complement expression in mesenchymal cells across bacterial and viral infections in the lung 2248926

Abstract

Abstract Introduction We have recently identified the lung mesenchyme as a potent source of complement proteins during homeostasis. However, the changes in the complement transcriptomic profile in the mesenchyme in the context of infections has not yet been elucidated. Here, we show that mesenchymal cells express a defined pattern of complement genes during respiratory bacterial and viral infections. Methods Single cell RNA-sequencing data from selected published studies in murine experimental lung infection with Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, influenza, and SARS-CoV-2 that included mesenchymal cells were analyzed. The raw counts data were retrieved from NCBI GEO and imported into RStudio/R (v4.3.1) and processed using Seurat (v5.0.1). Results Uninfected mesothelial cells exhibited high expression of classical pathway genes such as C1ra, C1s, C3, Serping1 (C1-INH), and Cfh, while fibroblasts highly expressed Serping1 and Cfh, consistent with our previous findings. During pneumococcal pneumonia, mesothelial cells showed downregulation of C2, C4b and Cfh expression, and upregulation of Cfb, whereas fibroblasts showed elevated expression of C3, Cfb and C4b, and repression of Cfh versus uninfected cells. Similar expression patterns in these cell types, though not always statistically significant, were observed in the other bacterial and viral infection models analyzed. As mesenchymal cells modulate inflammation and tissue repair through extracellular matrix (ECM) remodeling, we also explored ECM, collagen and cytokine expression. Across all infection models except Klebsiella, fibroblasts expressed higher levels of Timp1 (up to 100-fold), Col4a1, and Col4a2, while Stat1 was elevated in S. pneumoniae and viral infections. Conclusion Our study elucidates a cell-specific pattern of complement, ECM and cytokine/chemokine gene expression within lung mesenchymal cells during bacterial and viral infections and highlights a potential role for complement-driven ECM remodeling. Funding Source This work was funded by the National Institutes of Health (R01HL166588 to M.B.). Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)